EP3448852A1 - Nouveaux composés hétérocycliques comme inhibiteurs de la tyrosine kinase bcr-abl - Google Patents

Nouveaux composés hétérocycliques comme inhibiteurs de la tyrosine kinase bcr-abl

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Publication number
EP3448852A1
EP3448852A1 EP17788800.5A EP17788800A EP3448852A1 EP 3448852 A1 EP3448852 A1 EP 3448852A1 EP 17788800 A EP17788800 A EP 17788800A EP 3448852 A1 EP3448852 A1 EP 3448852A1
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European Patent Office
Prior art keywords
substituted
unsubstituted
mmol
compound
mixture
Prior art date
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EP17788800.5A
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German (de)
English (en)
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EP3448852A4 (fr
Inventor
Lianhai Li
Chunrong Yu
Haihong Huang
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Astar Biotech LLC
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Astar Biotech LLC
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Publication of EP3448852A1 publication Critical patent/EP3448852A1/fr
Publication of EP3448852A4 publication Critical patent/EP3448852A4/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/10—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 two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel heterocyclic compounds that inhibit the enzymatic activities of tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1.
  • ABL1 tyrosine kinase Abelson protein
  • ABL2 Abelson-related protein
  • the invention further provides a process for the preparation of compounds of the invention, their pharmaceutical compositions comprising the same as an active ingredient, methods using said compositions in the treatment of various disorders, and use of the compounds in the manufacture of a medicament in inhibition of the enzymatic activities of ABL1, ABL2 and related chimeric proteins.
  • Protein kinase are enzymes that modify other proteins by chemically adding phosphate groups to a specific residue thereof via phosphorylation. So far, about 500 protein kinase genes in the human genome are discovered and they constitute about 2%of all human genes. Based on their substrates of action, protein kinases can be grouped into three classes, which are: 1) . serine/threonine-specific protein kinases which perform phosphorylation on serine and/or threonine residues; 2) tyrosine-specific protein kinases which perform phosphorylation on tyrosine residues; and 3) . protein kinases which perform phosphorylation on both tyrosine and serine/threonine residues.
  • a major role played by protein kinases is to mediate the signal transduction from the cell surface to the nucleus in response to a variety of extracellular stimuli. Through this, they play a key role in regulating normal cellular phenomena, including cell division, proliferation, differentiation, apoptosis, cell mobility, mitogenesis, etc. ; However, their regulating mechanism directly or indirectly interrupted by some factors such as mutation, overexpression or abnormal activation of kinase enzyme, and overproduction or underproduction of growth factors or cytokines which affect up-stream or down-stream signaling. In case these happen, disease conditions can develop; and hence they are closely related with various diseases.
  • kinase-related diseases examples include: autoimmune disorders such as atopic dermatitis, asthma, rheumatoid arthritis, Crohn's disease, psoriasis, Crouzon syndrome, achondroplasia, and thanatophoric dysplasia; cancer such as prostate cancer, colorectal cancer, breast cancer, brain and throat cancer, leukemia and lymphoma; diabetes; restenosis; atherosclerosis; renal and hepatic fibrosis; myeloproliferative disorder and lymphoproliferative disorder; and eye disease. Therefore, it is expected that those diseases caused by kinase up-regulation or mutation may be mediated by selectively inhibiting the mechanism of kinase. This leads to tremendous efforts to discover various protein kinase inhibitors in the fields of medicine and chemistry.
  • Cancer is a disease resulting from an abnormal growth of tissue. Certain cancers have the potential to invade into local tissues and also metastasize to distant organs. This disease can develop in a wide variety of different organs, tissues and cell types. Therefore, the term “cancer” refers to a collection of over a thousand different diseases.
  • Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene (previous symbol ABL) located on chromosome 9 [Szczylik et al., Science, 1991, 253, P562-5] .
  • the ABL1 proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that has been implicated in processes of cell differentiation, cell division, cell adhesion, and stress response.
  • Activity of ABL1 protein is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABL1 into an oncogene.
  • the t (9; 22) translocation results in the head-to-tail fusion of the BCR and ABL1 genes, leading to a fusion gene present in all cases of chronic myelogenous leukemia.
  • the DNA-binding activity of the ubiquitously expressed ABL1 tyrosine kinase is regulated by CDC2-mediated phosphorylation, suggesting a cell cycle function for ABL1.
  • ABL1 Mutations in the ABL1 gene are a characteristic abnormality in chronic myelogenous leukemia (CML) and rarely in some other leukemia forms.
  • CML chronic myelogenous leukemia
  • the gene is activated by being translocated within the BCR (breakpoint cluster region) gene on chromosome 22.
  • BCR-ABL This new fusion gene, BCR-ABL, encodes an unregulated, cytoplasm-targeted tyrosine kinase, which activates mediators of the cell cycle regulation system, that allows the cells to proliferate without being regulated by cytokines. This, in turn, allows the cell to become cancerous.
  • the BCR-ABL protein inevitably becomes a drug target of CML treatment. It can be inhibited by various small molecules.
  • drugs that inhibit the tyrosine kinase activity of BCR-ABL1 via an ATP-competitive mechanism such as (imatinib) , (nilotinib) and (dasatinib) , are effective in the treatment of CML.
  • drug resistance happens to some patients and cause disease relapse due to the emergence of drug-resistant clones, in which mutations in the SH1domain compromise inhibitor binding.
  • BCR-ABL1 fusion proteins are causative in a percentage of acute lymphocytic leukemias, and drugs targeting ABL kinase activity also have utility in this indication.
  • drugs targeting ABL kinase activity also have utility in this indication.
  • compounds that can inhibit the BCR-ABL protein activities via a different binding mode might have the potential to overcome the resistance and expanding the treatment choice for AML patients.
  • allosteric inhibitors agents targeting the myristoyl binding site have potential for the treatment of BCR-ABL1 disorders [Zhang et al., Nature, 2010, 463, P501-6] .
  • an allosteric inhibitor that binds to the myristoyl binding site might be useful to prevent the emergence of drug resistance from ATP inhibitor.
  • a combination treatment using both types of inhibitor can be developed for the treatment of BCR-ABL1 related disorders. This might leads to more effective treatment for the AML patients and minimizes the rate of disease relapse.
  • inhibitors of ABL1 kinase activity have the potential to be used as therapies for the treatment of metastatic invasive carcinomas and viral infections such as pox and Ebola viruses.
  • the compounds from the present invention also have the potential to treat or prevent diseases or disorders associated with abnormally activated kinase activity of wild-type ABL1, including non-malignant diseases or disorders, such as CNS diseases in particular neurodegenerative diseases (for example Alzheimer's, Parkinson's diseases) , motoneuroneuron diseases (amyotophic lateral sclerosis) , muscular dystrophies, autoimmune and inflammatory diseases (diabetes and pulmonary fibrosis) , viral infections, prion diseases.
  • CNS diseases in particular neurodegenerative diseases (for example Alzheimer's, Parkinson's diseases) , motoneuroneuron diseases (amyotophic lateral sclerosis) , muscular dystrophies, autoimmune and inflammatory diseases (diabetes and pulmonary fibrosis) , viral infections, prion diseases.
  • the present invention provides compounds of Formula I:
  • R 1 , R 2 , R 3 , R 4 , L, Q, and Z is as defined and described herein.
  • the present invention provides a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
  • the present invention provides a method of treating a disease in an animal, especially in a human, in which modulation of the enzymatic activities of tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1 can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomer and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
  • ABL1 tyrosine kinase Abelson protein
  • ABL2 Abelson-related protein
  • BCR-ABL1 BCR-ABL1
  • the present invention provides the use of a compound of Formula I in the manufacture of a medicament for treating a disease in an animal, especially in a human, in which the enzymatic activities of tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1 contributes to the pathology and/or symptomology of the disease.
  • ABL1 tyrosine kinase Abelson protein
  • ABL2 Abelson-related protein
  • BCR-ABL1 related chimeric proteins
  • the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomer and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.
  • novel heterocyclic compounds in accordance with the present invention can selectively and effectively modulate wild and/or mutated the enzymatic activities of tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1activity.
  • ABL1 tyrosine kinase Abelson protein
  • ABL2 Abelson-related protein
  • BCR-ABL1activity BCR-ABL1activity
  • heterocyclic compounds that inhibit the enzymatic activities of tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1 in accordance with the present invention may be useful for prevention or treatment of diseases that are mediated by wild or one or more tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1 mutants such as cancers or tumors include those described herein.
  • some compounds of this invention have better in vivo efficacy, some have better bioavailability, some have less activity against hERG channel.
  • the present invention also includes all suitable isotopic variations of the compounds of the invention, or pharmaceutically acceptable salts thereof.
  • An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that may be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of hydrogen, carbon, nitrogen and oxygen such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S, 18 F, 37 C1 and 123 I.
  • isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies.
  • 3 H and 14 C isotopes may be used for their ease of preparation and detectability.
  • substitution with isotopes such as 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.
  • Isotopic variations of the compounds of the invention or pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.
  • the present invention provides a compound of formula (I) :
  • Each -R 1 is selected from -SF 5 , -CF 3 , -CF 2 Cl, -CF 2 Br, -CF 2 CF 3 , -CF 2 CF 2 Cl, -CF (CF 3 ) 2 , -CF 2 H, -CF 2 CF 2 H, -CH (CF 3 ) 2 ;
  • Each -R 2 is selected from -H, -F, -Cl, -Br;
  • Each R 3 is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl;
  • Each -R 4 is selected from a moiety listed in following Table 1, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl;
  • each -R is selected from -F, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl;
  • Each R O is selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl;
  • R N1 and R N2 are independently selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl;
  • Each R N0 is selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl;
  • Each R P is selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl;
  • R 1 , R 2 , R 3 , R 4 , L, and Z is as defined and described herein;
  • the present invention provides a compound of formula (II) wherein -R 2 is -H, thereby forming a compound of formula (III)
  • R 1 , R 3 , R 4 , L, and Z is as defined and described herein;
  • R 1 , R 3 , R 4 , and L is as defined and described herein;
  • R 1 , R 3 , R 4 , R Z and L is as defined and described herein;
  • alkyl refers to saturated hydrocarbon groups in a straight, branched, or cyclic configuration or any combination thereof, and particularly contemplated alkyl groups include those having ten or less carbon atoms, especially 1-6 carbon atoms and lower alkyl groups having 1-4 carbon atoms.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, cyclopropylmethyl, etc.
  • Alkyl groups can be unsubstituted, or they can be substituted to the extent that such substitution makes sense chemically.
  • alkenyl refers to an alkyl as defined above having at least two carbon atoms and at least one carbon-carbon double bond.
  • particularly contemplated alkenyl groups include straight, branched, or cyclic alkenyl groups having two to ten carbon atoms (e.g., ethenyl, propenyl, butenyl, pentenyl, etc. ) or 5-10 atoms for cyclic alkenyl groups.
  • Alkenyl groups are optionally substituted by groups suitable for alkyl groups as set forth herein.
  • alkynyl refers to an alkyl or alkenyl as defined above and having at least two (preferably three) carbon atoms and at least one carbon-carbon triple bond.
  • alkynyls include straight, branched, or cyclic alkynes having two to ten total carbon atoms (e.g., ethynyl, propynyl, butynyl, cyclopropylethynyl, etc. ) .
  • Alkynyl groups are optionally substituted by groups suitable for alkyl groups as set forth herein.
  • cycloalkyl refers to a cyclic alkane (i.e., in which a chain of carbon atoms of a hydrocarbon forms a ring) , preferably including three to eight carbon atoms.
  • exemplary cycloalkanes include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyls also include one or two double bonds, which form the "cycloalkenyl” groups. Cycloalkyl groups are optionally substituted by groups suitable for alkyl groups as set forth herein.
  • aryl or "aromatic moiety” as used herein refers to an aromatic ring system, which may further include one or more non-carbon atoms. These are typically 5-6 membered isolated rings, or 8-10 membered bicyclic groups, and can be substituted.
  • contemplated aryl groups include (e.g., phenyl, naphthyl, etc. ) and pyridyl.
  • Further contemplated aryl groups may be fused (i.e., covalently bound with 2 atoms on the first aromatic ring) with one or two 5-or 6-membered aryl or heterocyclic group, and are thus termed "fused aryl” or "fused aromatic” .
  • Aromatic groups containing one or more heteroatoms (typically N, O or S) as ring members can be referred to as heteroaryl or heteroaromatic groups.
  • Typical heteroaromatic groups include monocyclic C 5-6 aromatic groups such as pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, and imidazolyl and the fused bicyclic moieties formed by fusing one of these monocyclic groups with a phenyl ring or with any of the heteroaromatic monocyclic groups to form a C 8-10 bicyclic group such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl,
  • any monocyclic or fused ring bicyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system is included in this definition. It also includes bicyclic groups where at least the ring which is directly attached to the remainder of the molecule has the characteristics of aromaticity. Typically, the ring systems contain 5-12 ring member atoms.
  • heterocycle As also used herein, the terms “heterocycle” , “cycloheteroalkyl” , and “heterocyclic moieties” are used interchangeably herein and refer to any compound in which a plurality of atoms form a ring via a plurality of covalent bonds, wherein the ring includes at least one atom other than a carbon atom as a ring member.
  • heterocyclic rings include 5-and 6-membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine, indole, pyridine, thiazole, tetrazole etc. ) .
  • these rings typically contain 0-1 oxygen or sulfur atoms, at least one and typically 2-3 carbon atoms, and up to four nitrogen atoms as ring members.
  • heterocycles may be fused (i.e., covalently bound with two atoms on the first heterocyclic ring) to one or two carbocyclic rings or heterocycles, and are thus termed "fused heterocycle” or “fused heterocyclic ring” or “fused heterocyclic moieties” as used herein.
  • fused heterocycle or "fused heterocyclic ring” or “fused heterocyclic moieties” as used herein.
  • ring is aromatic, these can be referred to herein as 'heteroaryl' or heteroaromatic groups.
  • Heterocyclic groups that are not aromatic can be substituted with groups suitable for alkyl group substituents, as set forth above.
  • Aryl and heteroaryl groups can be substituted where permitted.
  • imidazopyridine or “imidazopyrimidine” or “thiazopyridine” or “thiazopyrimidine” herein refer to any compound in which the two designated heterocyclic rings are fused by any two adjacent atoms on the two heterocyclic rings.
  • alkoxy refers to a hydrocarbon group connected through an oxygen atom, e.g., -O-R OS , wherein the hydrocarbon portion R O may have any number of carbon atoms, typically 1-10 carbon atoms, may further include a double or triple bond and may include one or two oxygen, sulfur or nitrogen atoms in the alkyl chains, and can be substituted with aryl, heteroaryl, cycloalkyl, and/or heterocyclyl groups.
  • suitable alkoxy groups include methoxy, ethoxy, propyloxy, isopropoxy, methoxyethoxy, benzyloxy, allyloxy, and the like.
  • alkylthio refers to alkylsulfides of the general formula -S-R SS1 , wherein the hydrocarbon portion R SS1 is as described for alkoxy groups.
  • contemplated alkylthio groups include methylthio, ethylthio, isopropylthio, methoxyethylthio, benzylthio, allylthio, and the like.
  • alkylamino refers to amino groups where one or both hydrogen atoms are replaced by a hydrocarbon group to form N (R NS1 ) (R NS2 ) as described above, wherein the amino nitrogen "N" can be substituted by one R NS group (referred as R NS1 , as described and defined as above) or two R NS groups (referred as R NS1 and R NS2 , as described and defined as above) .
  • R NS1 R NS1
  • R NS1 and R NS2 as described and defined as above
  • Exemplary alkylamino groups include methylamino, dimethylamino, ethylamino, diethylamino, etc.
  • substituted amino refers to amino groups where one or both hydrogen atoms are replaced by a hydrocarbon group R NS as described above, wherein the amino nitrogen “N” can be substituted by one or two R NS groups as described above.
  • D can be H, Me, Et, isopropyl, propyl, butyl, C 1-4 alkyl substituted with -OH, -OMe, or NH 2 , phenyl, halophenyl, alkylphenyl, and the like.
  • aryloxy refers to an aryl group connecting to an oxygen atom, wherein the aryl group may be further substituted.
  • suitable aryloxy groups include phenyloxy, etc.
  • arylthio refers to an aryl group connecting to a sulfur atom, wherein the aryl group may be further substituted.
  • suitable arylthio groups include phenylthio, etc.
  • hydrocarbon portion of each alkoxy, alkylthio, alkylamino, and aryloxy, etc. can be substituted as appropriate for the relevant hydrocarbon moiety.
  • halogen refers to fluorine, chlorine, bromine and iodine. Where present as a substituent group, halogen or halo typically refers to F or Cl or Br, more typically F or Cl.
  • haloalkyl refers to an alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group.
  • groups include, without limitation, fluoroalkyl groups, such as fluoroethyl, trifluoromethyl, difluoromethyl, trifluoroethyl and the like.
  • haloalkoxy refers to the group alkyl-O-wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.
  • sulfonyl refers to the group SO 2 -alkyl, SO 2 -substituted alkyl, SO 2 -alkenyl, SO 2 -substituted alkenyl, SO 2 -cycloalkyl, SO 2 -substituted cycloalkyl, SO 2 -cycloalkenyl, SO 2 -substituted cycloalkenyl, SO 2 -aryl, SO 2 -substituted aryl, SO 2 -heteroaryl, SO 2 -substituted heteroaryl, SO 2 -heterocyclic, and SO 2 -substituted heterocyclic, wherein each alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, ary
  • sulfonylamino refers to the group -NR NS1 SO 2 R NS2 , wherein R NS1 and R NS2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and wherein R NS1 and R NS2 may optionally join together with the atoms bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl
  • aminosulfonyl refers to the group -SO 2 NR NS1 R NS2 , wherein each R NS1 and R NS2 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and wherein R NS1 and R NS2 may optionally join together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted
  • R NS1 and R NS2 are independently selected from hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, aryl, fused aryl, heteroaryl, fused heterocycle, a C 3-8 carbocyclic ring or a C 4-8 heterocyclic ring, saturated or unsaturated, wherein suitable, a substituted or unsubstituted alkyl, alkenyl, alkynyl can optionally contain a heteroatom selected from N, O, P, and S in place of a carbon atom; wherein R NS1 and R NS2 may join together to form a 4, 5, 6 or 7-membered heterocyclic ring, when suitable, a carbon atom in the ring
  • all of the above-defined groups may further be substituted with one or more substituents, which may in turn be substituted with hydroxy, amino, cyano, C 1-4 alkyl, halo, or C 1-4 haloalkyl.
  • substituents may in turn be substituted with hydroxy, amino, cyano, C 1-4 alkyl, halo, or C 1-4 haloalkyl.
  • a hydrogen atom in an alkyl or aryl can be replaced by an amino, halo or C 1-4 haloalkyl or alkyl group.
  • substituted refers to a replacement of a hydrogen atom of the unsubstituted group with a functional group
  • ionic groups e.g., -NH 3 +
  • halogens e.g., -F, -Cl, -Br, -I
  • NHCOR NHCONH 2 , OCH 2 COOH, OCH 2 CONH 2 , OCH 2 CONHR, NHCH 2 COOH, NHCH 2 CONH 2 , NHSO 2 R, OCH 2 -heterocycles, -PO 3 H, -SO 3 H, amino acids, and all chemically reasonable combinations thereof.
  • substituted also includes multiple degrees of substitution, and where multiple substituents are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties.
  • a group that is substituted has 1 , 2, 3, or 4 substituents, 1 , 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.
  • arylalkyloxycarbonyl refers to the group (aryl) - (alkyl) -O-C (O) -.
  • any of the groups disclosed herein which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the subject compounds include all stereochemical isomers arising from the substitution of these compounds.
  • pharmaceutically acceptable salt means a salt which is acceptable for administration to a patient, such as a mammal, such as human (salts with counterions having acceptable mammalian safety for a given dosage regime) .
  • Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-5 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • salt thereof means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like.
  • the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient.
  • salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.
  • the compounds and compositions described herein can be administered to a subject in need of treatment for a cell proliferation disorder such as cancer, particularly cancers selected from leukemia, lymphoma, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, head and neck cancers, and pancreatic cancer.
  • a cell proliferation disorder such as cancer, particularly cancers selected from leukemia, lymphoma, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, head and neck cancers, and pancreatic cancer.
  • the subject is typically a mammal diagnosed as being in need of treatment for one or more of such proliferative disorders, and frequently the subject is a human.
  • the methods comprise administering an effective amount of at least one compound of the invention; optionally the compound may be administered in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful for treating the cancer or proliferative disorder afflicting the particular subject.
  • provided compounds are selective inhibitors of tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1.
  • ABL1 tyrosine kinase Abelson protein
  • ABL2 Abelson-related protein
  • BCR-ABL1 BCR-ABL1.
  • a provided compound selectively inhibits at least one kinase selected from tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1.
  • ABL1 tyrosine kinase Abelson protein
  • ABL2 Abelson-related protein
  • BCR-ABL1 BCR-ABL1.
  • the at least one kinase is tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1.
  • ABL1 tyrosine kinase Abelson protein
  • ABL2 Abelson-related protein
  • BCR-ABL1 BCR-ABL1.
  • provided compounds do not appreciably inhibit, either reversibly or irreversibly, other protein kinases.
  • a provided compound is selective for inhibiting at least one kinase selected from tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1as compared to off-target protein kinases thereby avoiding effects and toxicities associated with inhibition thereof.
  • a provided compound is synthesized using one or more of the following steps and intermediates are as defined and described in classes and subclasses herein.
  • Scheme 1 Provided in Scheme 1 is a general method for preparation of intermediate IN-1.
  • a certain carboxylic acid such as SM-C
  • the corresponding acid chloride was formed.
  • the reaction can be performed in the presence or absence of an amide, especially DMF.
  • the newly formed acid chloride then reacted with a suitable aniline or 3-aminopyridine derivative in the presence or absence of a base to form the corresponding amide IN-1.
  • substituted or unsubstituted 5-10 membered heteroaryl metallic reagent, boron derivative, silicon derivative or substituted or unsubstituted 5-10 membered heteroaryl metallic reagent, boron derivative, silicon derivative can selectively react with IN-1 at the C-X 4 bond and formed the C-R 4 bond when catalyzed by suitable transition metal complex;
  • Each -R 4 is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl.
  • each -R is selected from -F, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl;
  • IN-1 can selectively react with substituted or unsubstituted 5-10 membered heteroaryl metallic reagent, boron derivative, silicon derivative or substituted or unsubstituted 5-10 membered heteroaryl metallic reagent, boron derivative, silicon derivative at the C-X 3 bond and formed the C-R 3 bondwhen catalyzed by suitable transition metal complex;
  • Each -R 3 is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl.
  • substituted or unsubstituted 5-10 membered heteroaryl metallic reagent, boron derivative, silicon derivative or substituted or unsubstituted 5-10 membered heteroaryl metallic reagent, boron derivative, silicon derivative can selectively react with IN-3 at the C-X 4 bond and formed the C-R 4 bond when catalyzed by suitable transition metal complex;
  • Each -R 4 is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl.
  • further reaction need to be performed to remove protective group (s) carried by R 3 and/or R 4 to convert the coupling product into the final compound of formula (I) .
  • Scheme 5 Provided in Scheme 5 is an alternative general method for preparation of the compound of formula (I) from IN-2.
  • IN-2 Catalyzed by suitable transition metal complex, IN-2 can react with substituted or unsubstituted 5-10 membered heteroaryl metallic reagent, boron derivative, silicon derivative or substituted or unsubstituted 5-10 membered heteroaryl metallic reagent, boron derivative, silicon derivative at the C-X 3 bond and formed the C-R 3 bond;
  • Each -R 3 is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl.
  • the compounds of the invention and their pharmaceutically acceptable salts exhibit valuable pharmacological properties when tested in vitro in cell-free kinase assays and in cellular assays, and are therefore useful as pharmaceuticals.
  • the compound of formula (I) of the present invention may also form a pharmaceutically acceptable organic or inorganic acid addition salts.
  • Such salts are acid addition salts formed by acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.
  • the invention provides a composition comprising a compound of this invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • An amount of compound in a composition of this invention is such that is effective to measurably inhibit a protein kinase, particularly to inhibit tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1 selectively as compared to other kinases (e.g., ErbB2, ErbB4, a TEC-kinase, and/or JAK3) .
  • an amount of compound in a provided composition is such that is effective to measurably inhibit tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1 selectively as compared to other protein kinases (e.g., ErbB2, ErbB4, a TEC-kinase, and/or JAK3) .
  • ABL1 Abelson protein
  • ABL2 Abelson-related protein
  • JAK3 protein kinases
  • the amount of compound in a provided composition is such that is effective to measurably inhibit tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1 selectively as compared other kinases, in a biological sample or in a patient.
  • ABL1 Abelson protein
  • ABL2 Abelson-related protein
  • related chimeric proteins in particular BCR-ABL1 selectively as compared other kinases
  • the amount of compound in a provided composition is such that is effective to measurably inhibit tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1 selectively as compared to other protein kinases (e.g., ErbB2, ErbB4, a TEC-kinase, and/or JAK3) , in a biological sample or in a patient.
  • ABL1 Abelson protein
  • ABL2 Abelson-related protein
  • JAK3 protein e.g., JAK3
  • a composition of this invention is formulated for administration to a patient in need of such composition.
  • a composition of this invention is formulated for oral administration to a patient.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block poly
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent for example as a solution in 1, 3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-
  • compositions of this invention are formulated for oral administration.
  • compositions of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 -100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • compounds of Formula (I) may inhibit tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1.
  • ABL1 tyrosine kinase Abelson protein
  • ABL2 Abelson-related protein
  • BCR-ABL1 BCR-ABL1.
  • the compounds of the invention may also be useful in the treatment and/or prevention of acute or chronic inflammatory diseases or disorders or autoimmune diseases e.g. rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, diabetes (type I and II) and the disorders associated therewith, respiratory diseases such as asthma or inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically-mediated disorders or illnesses, inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and further eczematous dermatitis, seborrhoeic dermatitis) , s inflammatory eye diseases, e.g. Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease or ulcerative co
  • the present invention provides:
  • a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof in particular a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof for use as a tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1 inhibitor for example for use in any of the particular indications hereinbefore set forth;
  • ABL1 Abelson protein
  • ABL2 Abelson-related protein
  • BCR-ABL1 inhibitor for example for use in any of the particular indications hereinbefore set forth;
  • composition e.g. for use in any of the indications hereinbefore set forth, comprising a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof as active ingredient together with one or more pharmaceutically acceptable diluents or carriers;
  • the method comprise co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof and one or more further drug substances, said further drug substance being useful in any of the particular indications set forth hereinbefore;
  • a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease or condition in which tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1 activation plays a role or is implicated;
  • ABL1 tyrosine kinase Abelson protein
  • ABL2 Abelson-related protein
  • BCR-ABL1 activation plays a role or is implicated
  • the disease to be treated is selected from anaplastic large cell lymphoma, non-Hodgkin's lymphomas, inflammatory myofibroblastic tumors, neuroblastomas and neoplastic diseases;
  • Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP or GTP to a tyrosine residue located on a protein substrate. Receptor tyrosine kinases act to transmit signals from the outside of a cell to the inside by activating secondary messaging effectors via a phosphorylation event. A variety of cellular processes are promoted by these signals, including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, and cell survival.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors) . Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1 is known to play a role.
  • the present invention relates to a method of treating or lessening the severity of a disease or condition selected from a proliferative disorder, wherein said method comprises administering to a patient in need thereof a compound or composition according to the present invention.
  • the present invention provides a method for treating or lessening the severity of one or more disorders selected from a cancer.
  • the cancer is associated with a solid tumor.
  • the cancer is breast cancer, glioblastoma, lung cancer, cancer of the head and neck, colorectal cancer, bladder cancer, or non-small cell lung cancer.
  • the present invention provides a method for treating or lessening the severity of one or more disorders selected from squamous cell carcinoma, salivary gland carcinoma, ovarian carcinoma, pancreatic cancer, or other cancers including lung, colon, breast, prostate, liver, pancreas, brain, kidney, stomach, skin, and bone, etc.
  • the present invention provides a method for treating or lessening the severity of neurofibromatosis type I (NF1) , neurofibromatosis type II (NF2) Schwann cell neoplasms (e.g. MPNST's) , or Schwannomas.
  • NF1 neurofibromatosis type I
  • NF2 neurofibromatosis type II
  • MPNST's neurofibromatosis type II
  • Schwann cell neoplasms e.g. MPNST's
  • Schwannomas e.g. MPNST's
  • the compounds and compositions, according to the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops) , bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg or from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils) , glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U. S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, terminal (heat) sterilization, or sterilization via ionizing radiationor by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly (orthoesters) and poly (anhydrides) .
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol mono
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • a solid composition is a liquid filled hard gelatin capsule or solid dispersion.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • additional therapeutic agents which are normally administered to treat that condition, may also be present in the compositions of this invention.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as "appropriate for the disease, or condition, being treated. "
  • compounds of the present invention are administered in combination with chemotherapeutic agents to treat proliferative diseases and cancer.
  • chemotherapeutic agents include, but are not limited to, Adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, platinum derivatives, taxane (e.g , paclitaxel) , vinca alkaloids (e.g., vinblastine) , anthracyclines (e.g., doxorubicin) , epipodophyllotoxins (e.g., etoposide) , cisplatin, an mTOR inhibitor (e.g., a rapamycin) , methotrexate, actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate, metoprine, cyclosporine, daunorubicin,
  • an mTOR inhibitor e.g.,
  • compounds of the present invention are administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, camptothecin, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin,
  • agents the inhibitors of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as donepezil hydrochloride and rivastigmine treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., and ) , glatiramer acetate and mitoxantrone; treatments for asthma such as albuterol and montelukast agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as
  • compounds of the present invention are administered in combination with a monoclonal antibody or a siRNA therapeutic.
  • Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen.
  • those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the term “combination, “ “combined, “ and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a provided compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions of this invention should be formulated so that a dosage of between 0.01 -100 mg/kg body weight/day of an inventive can be administered.
  • compositions which comprise an additional therapeutic agent that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 -1, 000 ⁇ g/kg body weight/day of the additional therapeutic agent can be administered.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50%to 100%of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • an implantable medical device such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • Vascular stents for example, have been used to overcome restenosis (re -narrowing of the vessel wall after injury) .
  • patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor.
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • Section 1.2 The synthesis of intermediates IN-2
  • Method 1 A round-bottom flask was charged with IN-1-03 (5g, 12.14 mmol) , pyridin-3-ylboronic acid (2.08 g, 17 mmol) , K 3 PO 4 (3.61, 17 mmol) , and [Pd (dppf) Cl 2 ] . CH 2 Cl 2 (3.03 g, 3.72 mmol) and the system was put under vacuum, and a mixture of DME/H2O/EtOH (7/3/2) (200 mL) was added via syringe under vacuum. The system was put under N 2 atmosphere with a nitrogen balloon. The reaction was heated at reflux (85°C) for 12 h.
  • Method 2 A mixture of IN-1-03 (40.0 g, 87.14 mmol) , pyridin-3-ylboronic acid (12.85 g, 104.57 mmol) , K 2 CO 3 (24.09 g) , Tetrakis (triphenylphosphine) palladium (0) (5.04 g, 4.36 mmol) was charged in a flask and then a mixture of 218 mL of 1, 4-dioxane and 87 mL of water was charged. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. Then vacuum was applied to the system until sight bubbling was observed again.
  • AM-01 (3S) -3- (S-methylsulfonimidoyl) pyrrolidine
  • Step 2 (R) -benzyl 3- ( (methylsulfonyl) oxy) pyrrolidine-1-carboxylate
  • Step 4 (S) -benzyl 3- (S-methyl-N-tosylsulfinimidoyl) pyrrolidine-1-carboxylate
  • Step 5 (3S) -benzyl 3- (S-methyl-N-tosylsulfonimidoyl) pyrrolidine-1-carboxylate
  • AM-02 (3R) -3- (S-methylsulfonimidoyl) pyrrolidine
  • Step 1 (S) -benzyl 3- (methylsulfonyl) pyrrolidine-1-carboxylate
  • Step 2 ( (S) -3- (methylsulfonyl) pyrrolidine
  • AM-04 (R) -3- (methylsulfonyl) pyrrolidine
  • Section 2.1 The synthesis of Examples
  • Example 001 By following the procedure described above for the synthesis of Example 001, the title compound was synthesized (12.4 mg, 8%yield) from 5-bromo-6- ( (R) -3- (S-methylsulfonimidoyl) pyrrolidin-1-yl) -N- (4- (trifluoromethoxy) phenyl) nicotinamide (108 mg) .
  • Example 001 The title compound was synthesized by following the procedure described above for the synthesis of Example 001 from (S) -5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (3- (methylsulfonyl) pyrrolidin-1-yl) nicotinamide.
  • the crude was purified by flash chromatography (0-100%Solvent B/DCM, while solvent B is a 9/1 mixture of EtOAC/MeOH) to afford the title compound (17 mg, 16%yield) .
  • Example 001 The title compound was synthesized by following the procedure described above for the synthesis of Example 001 from (R) -5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (3- (methylsulfonyl) pyrrolidin-1-yl) nicotinamide.
  • the crude was purified by flash chromatography (0-100%Solvent B/DCM, while solvent B is a 9/1 mixture of EtOAC/MeOH) to afford the title compound (103 mg, 37 %yield) .
  • a scintillation vial was charged with the amide IN-2-10 (0.1364 g, 0.30 mmol) , 1- (tetrahydro-2H-pyran-2-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.1229 g, 0.44 mmol) , K 2 CO 3 (0.94 g, 0.68 mmol) , and [Pd (PPh 3 ) 2 Cl 2 ] (0.0477 g, 0.07 mmol) . Then, the system was put under vacuum and a mixture of dioxane/water was added (10/2 mL) via syringe under vacuum.
  • a reaction vial was charged with IN-3-03 (0.1 g, 0.20 mmol) , pyridin-3-ylboronic acid (0.034 g, 0.27 mmol) , K 2 CO 3 (0.058g, 0.42 mmol) , and [Pd (PPh 3 ) 2 Cl 2 ] (0.029 g, 0.04 mmol) . Then the system was put under vacuum and a solvent mixture of 10%water in 1, 4-dioxane (10 mL) was added via syringe under vacuum. Then, the system was put under a N 2 atmosphere and the reaction was heated at reflux overnight. After cooling down to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (3x20mL) .
  • Example 013 N- (4- (chlorodifluoromethoxy) phenyl) -6-phenyl-5- (1H-pyrazol-5-yl) nicotinamide
  • Example 014 N- (4- (chlorodifluoromethoxy) phenyl) -5- (1H-pyrazol-5-yl) -6- (thiophen-3-yl) nicotinamide
  • Example 021 N- (4- (chlorodifluoromethoxy) phenyl) -5, 6-bis (1-methyl-1H-imidazol-5-yl) nicotinamide
  • Step 1 N- (4- (chlorodifluoromethoxy) phenyl) -2-hydrazinyl- [3, 3'-bipyridine] -5-carboxamide (IN-4-01)
  • Example 031 N- (4- (chlorodifluoromethoxy) phenyl) -2- (2-ethylphenyl) - [3, 3'-bipyridine] -5-carboxamide
  • Example 035 N- (4- (chlorodifluoromethoxy) phenyl) -5- (pyrimidin-5-yl) -6- (o-tolyl) nicotinamide
  • Example 037 N- (4- (chlorodifluoromethoxy) phenyl) -5, 6-di (1H-pyrazol-4-yl) nicotinamide
  • Example 038 5, 6-di (1H-pyrazol-5-yl) -N- (4- (trifluoromethoxy) phenyl) nicotinamide
  • Example 040 N- (4- (chlorodifluoromethoxy) phenyl) -5- (1H-pyrazol-5-yl) -6- (o-tolyl) nicotinamide
  • Example 039 (0.22 g, 0.46 mmol) , 65%of hydrazine (0.223 g, 4.64 mmol) , in 5 mL of 2-PrOH was heated reflux and stirred at this temperature overnight. The solvent was evaporated and the residue was redissolved in 15 mL of MeOH and evaporated to dryness to afford the title compound as a white solid. (226 mg, 100%yield) .
  • the title compound was prepared by following the procedure described for Example 48, from IN-3-07 (0.40 g, 60%purity, 0.56 mmol) , 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.233 g, 0.1.12 mmol) , K 2 CO 3 (0.464 g, 3.36 mmol) , Pd (DPPF) Cl 2 (62 mg, 0.08 mmol) .
  • the title compound was prepared by following the procedure described for Example 48, from IN-3-07 (0.40 g, 60%purity, 0.56 mmol) , 1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.233 g, 0.1.12 mmol) , K 2 CO 3 (0.464 g, 3.36 mmol) , Pd (DPPF) Cl 2 (62 mg, 0.08 mmol) .
  • the title compound was prepared by following the procedure described for Example 48, from IN-3-01 (0.15 g, 0.36 mmol) , 1- (tetrahydro-2H-pyran-2-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.203 g, 0.73 mmol) , K 2 CO 3 (0.303 g, 2.19 mmol) , Pd (DPPF) Cl 2 (40 mg, 0.05 mmol) .
  • Example 059 methyl 4- (5- ( (4- (chlorodifluoromethoxy) phenyl) carbamoyl) - [3, 3'-bipyridin] -2-yl) benzoate
  • Example 060 methyl 4- (5- ( (4- (chlorodifluoromethoxy) phenyl) carbamoyl) - [3, 3'-bipyridin] -2-yl) benzoate
  • Example 061 4- (5- ( (4- (chlorodifluoromethoxy) phenyl) carbamoyl) - [3, 3'-bipyridin] -2-yl) benzoic acid
  • Example 034 To a solution of Example 034 (153 mg, 0.31 mmol) and Et 3 N (0.258 mL, 1.86 mmol) in DCM (3 mL) in a reaction tube was added TFAA (130 mg, 0.62 mmol) dropwise and and the mixture was stirred at rt overnight. LCMS showed that reaction done. The reaction was worked up by the addition of sat NaHCO 3 /H 2 O, extracted with DCM and dried over Na 2 SO 4 , filtered and evaporated. The residue was purified by flash chromatography (0-100%solent B/hexanes, while solvent B is a solvent mixture of 10% MeOH in EtOAc) to afford a dark solid.
  • Example 063 3- (5- ( (4- (chlorodifluoromethoxy) phenyl) carbamoyl) - [3, 3'-bipyridin] -2-yl) benzoic acid
  • the reaction was work up by evaporation and the residue was redissolved in water and treated with 0.20 mL of AcOH, extracted with EtOAc and dried over Na 2 SO 4 , filtered and evaporated onto 4 g of silica gel and purified by flash chromatography (0-100%solent B/hexanes, while solvent B is a solvent mixture of 30% MeOH in EtOAc) to afford the desired as a colorful gum.
  • the gum was further purified by C 18 flash with a 43 g C 18 column (30-95%MeCN/water) and the impurity still existed.
  • K562 cells was purchased from ATCC and maintained in RPMI 1640 (Invitrogen) supplemented with 10%fetal bovine serum and penicillin/streptomycin.
  • BaF3/BCR-ABLT315I was constructed as described following. Total RNA was extracted from K-562 cells with Trizol reagent (Invitrogen, Carlsbad, CA) , according to the manufacturer’s protocol. First strand cDNA was synthesized by III Reverse Transcriptase (Invitrogen) , primed by Oligo dT primers. The BCR-ABL cDNA was amplified using PCR strategy and then ligated into the EcoRI site of the mammalian expression vector pSR ⁇ . Site mutation T315I was introduced into full length BCR-ABL by overlapping PCR with the primers containing the mutation site.
  • 293T cells were transiently transfected with pSR ⁇ vector containing BCR-ABLT315I to produce retrovirus. The viral supernatant was harvested at 48 h after transfection. Ba/F3 cells were incubated with retroviral supernatants containing 2 mg/ml polybrene (Sigma) and IL-3 (Invitrogen) . Stable transfectants were selected by maintaining cells in RPMI 1640 (Invitrogen) supplemented with 10%serum, penicillin/streptomycin (Invitrogen) , and 0.75 mg/ml G418 (Sigma) . IL-3 was removed to further select stably expressing cells, which were then confirmed by western blotting analysis.
  • MTT assays Tetrazolium-based proliferation assay were performed to determine the concentration of 50%growth inhibition. Briefly, cells were plated in triplicate at the density of 1.0x105 cells per well in 24-well microtiter plates and treated with serially diluted concentrations of ABL001 analogs (AST90-97, AST101-119) for 72 hour, the solvent DMSO as negative control. MTT uptake was assayed by measuring the absorbance at 570 nm. The mean was calculated for each concentration of the drug. GI 50 (50%growth inhibition) values are reported as the mean of three independent experiments.
  • TGI 1- [ (Vt end -Vt starting ) / (Vv end -Vv starting ) ] , wherein Vt end is the tumor volume at the end of treatment group, Vt starting is the tumor volume at the starting of treatment group, Vv end is the tumor volume at the end of vehicle group, Vv starting is the tumor volume at the starting of vehicle group.

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Abstract

La présente invention concerne un composé de formule (Ⅰ) ou un sel pharmaceutiquement acceptable de ce dernier, les variables étant décrites dans la description. L'invention concerne également un procédé de préparation des composés, leurs compositions pharmaceutiques comprenant ces composés comme ingrédients actifs, des procédés utilisant lesdites compositions dans le traitement de divers troubles, et l'utilisation des composés dans la fabrication d'un médicament destiné à inhiber les activités enzymatiques d'ABL1, ABL2 et des protéines chimères apparentées.
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WO2020087202A1 (fr) * 2018-10-29 2020-05-07 Merck Sharp & Dohme Corp. Modulateurs allostériques de 3-(1h-pyrazol-4-yl)pyridine du récepteur muscarinique m4 de l'acétylcholine
WO2021018194A1 (fr) * 2019-07-29 2021-02-04 Ascentage Pharma (Suzhou) Co., Ltd. Composés hétérocycliques utilisés en tant qu'inhibiteurs de bcr-abl
CN113121524B (zh) * 2019-12-31 2023-04-25 南京创济生物医药有限公司 杂环亚砜亚胺化合物及其中间体、制备方法和应用
CN114728943B (zh) * 2020-01-19 2024-12-06 正大天晴药业集团股份有限公司 作为bcr-abl抑制剂的化合物
WO2023051681A1 (fr) * 2021-09-30 2023-04-06 江苏豪森药业集团有限公司 Composé cyclique fusionné à quatre chaînons, son procédé de préparation et son utilisation
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