EP3448852A1 - Novel heterocyclic compounds as tyrosine kinase bcr-abl inhibitors - Google Patents

Novel heterocyclic compounds as tyrosine kinase bcr-abl inhibitors

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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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Prior art keywords
substituted
unsubstituted
mmol
compound
mixture
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EP17788800.5A
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German (de)
French (fr)
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EP3448852A4 (en
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/en
Publication of EP3448852A4 publication Critical patent/EP3448852A4/en
Withdrawn legal-status Critical Current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.

Abstract

Disclosed is a compound of Formula (Ⅰ) or a pharmaceutically acceptable salt thereof, wherein the variables are described herein. Also disclosed is a process for the preparation of compounds, 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.

Description

    NOVEL HETEROCYCLIC COMPOUNDS AS TYROSINE KINASE BCR-ABL INHIBITORS FIELD OF THE INVENTION
  • 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. 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.
    • BACKGROUND OF THE INVENTION
  • 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. Examples of such kinase-related diseases, to name a few but not limited to, are: 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.
  • Mutations in the ABL1 gene are a characteristic abnormality in chronic myelogenous leukemia (CML) and rarely in some other leukemia forms. In CML, the gene is activated by being translocated within the BCR (breakpoint cluster region) gene on chromosome 22. 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.
  • Thus, the BCR-ABL protein inevitably becomes a drug target of CML treatment. It can be inhibited by various small molecules. Currently, there are 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. Even though, as any kinase inhibitor, 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. In addition to CML, 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. Thus, 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.
  • It was reported that agents targeting the myristoyl binding site (referred as allosteric inhibitors) have potential for the treatment of BCR-ABL1 disorders [Zhang et al., Nature, 2010, 463, P501-6] . Potentially, an allosteric inhibitor that binds to the myristoyl binding site might be useful to prevent the emergence of drug resistance from ATP inhibitor. More important, 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.
  • Due to the broad involvement of ABL1 in various biological activities, 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.
  • SUMMARY OF THE INVENTION
  • In one aspect, the present invention provides compounds of Formula I:
  • or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, L, Q, and Z is as defined and described herein.
  • In a second aspect, 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.
  • In a third aspect, 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.
  • In a fourth aspect, 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.
  • In a fifth aspect, 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.
  • The 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. Therefore, the 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. Wherein 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. Examples of 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 2H, 3H, 11C, 13C, 14C, 15N, 170, 180, 35S, 18F, 37C1 and 123I. Certain isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. In particular examples, 3H and 14C isotopes may be used for their ease of preparation and detectability. In other examples, substitution with isotopes such as 2H 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.
    • DETAILED DESCRIPTION OF THE INVENTION
  • General Description of Compounds of the Invention
  • In certain embodiments, the present invention provides a compound of formula (I) :
  • or a pharmaceutically acceptable salt thereof, wherein:
  • Each -R1 is selected from -SF5, -CF3, -CF2Cl, -CF2Br, -CF2CF3, -CF2CF2Cl, -CF (CF3) 2, -CF2H, -CF2CF2H, -CH (CF3) 2；
  • Each -L- is selected from a bond, -CF2-, -O-, -S (＝O) m-, -NRLN-； wherein each -RLN is selected from -H, -CH3, -CF3, -CF2H； m is 0, 1, or 2；
  • Each -R2 is selected from -H, -F, -Cl, -Br；
  • Each -Q＝ is selected from -CH＝, -N＝；
  • Each -Z＝ is selected from -C (RZ) ＝, -N＝； wherein each -RZ is selected from -H, -F, -Cl, -Br, -ORO, -NRN1RN2；
  • Each R3 is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl；
  • Each -R4 is selected from a moiety listed in following Table 1, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl；
  • Table 1: Moieties that can be selected as -R4
  • When chemically making sense, the carbon-hydrogen bonds in the moieties listed in the above Table 1 can be replaced with one to three carbon-R groups, wherein each -R is selected from -F,  substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl；
  • Each RO is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl；
  • Each RN1 and RN2 are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl；
  • When chemically making sense, one or two carbon of the said substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-8 cycloalkyl may be replaced by -O-, -N (RN0) -, -S (＝O) m-, -P (RP) (＝O) -； m is 0, 1 or 2；
  • Each RN0 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl；
  • Each RP is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl；
  • In one certain embodiment, the present invention provides a compound of formula (I) wherein -Q＝ is -CH＝, thereby forming a compound of formula (II)
  • or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, L, and Z is as defined and described herein；
  • In another certain embodiment, the present invention provides a compound of formula (II) wherein -R2 is -H, thereby forming a compound of formula (III)
  • or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R4, L, and Z is as defined and described herein；
  • In one more certain embodiment, the present invention provides a compound of formula (III) wherein -Z＝ is -N＝, thereby forming a compound of formula (IIIa)
  • or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R4, and L is as defined and described herein；
  • In another more certain embodiment, the present invention provides a compound of formula (III) wherein -Z＝ is -C (RZ) ＝, thereby forming a compound of formula (IIIb)
  • or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R4, RZ and L is as defined and described herein；
  • General Definitions:
  • Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.
  • As used herein, "a" or "an" means "at least one" or "one or more" .
  • The term "alkyl" as used herein 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.
  • Exemplary 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. Typical substituents include, but are not limited to, halo, ＝O, ＝N-CN, ＝N-OROS, ＝NRNS0, -OROS, -NRNS1RNS2, -SRSS1, -SO2RSS2, -SO2NRNS1RNS2, -NRNS1SO2RSS2, -NRNS1C (＝O) NRNS1RNS2, -NRNS1C (＝O) OROS, -NRNS1C (＝O) RCS, -CN, -C (＝O) OROS, -C (＝O) NRNS1RNS2, -OC (＝O) RCS, -C (＝O) RCS, and -NO2, wherein: Each RSS1is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl； Each RSS2is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl； Each ROS is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl； Each RCS is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl； Each RNS1 and RNS2 are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl； When chemically making sense, one or two carbon of the said substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-8 cycloalkyl may be replaced by -O-, -N (RNS0) -, -S (＝O) 0-2-, -P (RPS) (＝O) -； Each RPS is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl； Each RNS0 is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, -CN, -OROS, -O (C (＝O) RCS) , -C (＝O) OROS) , -C (＝S) OROS) -O (C (＝S) RC) -N (RNS1) (RNS2) , -N (RNS1) (S (＝O) 1-2RSS2) , -N (RNS1) (S (＝O) 1-2NRNS1RNS2) , -N (RNS1) (C (＝O) RCS) , -N (RNS1) (C (＝O) NRNS1RNS2) , -N (RNS1) (C (＝S) RCS) , -N (RNS1) (C (＝S) NRNS1RNS2) , -S (＝O) 1-2RSS2, -S (＝O) 1-2NRNS1RNS2, or -C (＝O) NRNS1RNS2, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl； when exist as a pair, RNS1 and RNS2, RNS1 and RSS2, or RNS1 and RCS may join together to form a 3-8 membered ring system；
  • The term "alkenyl" as used herein refers to an alkyl as defined above having at least two carbon atoms and at least one carbon-carbon double bond. Thus, 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.
  • Similarly, the term "alkynyl" as used herein 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. Especially contemplated 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.
  • The term "cycloalkyl" as used herein 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. Thus, 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.
  • The term "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. Thus, 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 C5-6 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 C8-10 bicyclic group such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, pyrazolopyrimidyl, quinazolinyl, quinoxalinyl, cinnolinyl, and the like. 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.
  • 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.
  • Particularly contemplated 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. ) . Typically these rings 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. Further contemplated 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. Where the 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. Suitable substituents include, but are not limited to, Typical substituents include, but are not limited to, halo, -OROS, -NRNS1RNS2, -SRSS1, -SO2RSS2, -SO2NRNS1RNS2) , -NRNS1SO2RSS2, -NRNS1C (＝O) NRNS1RNS2, -NRNS1C (＝O) OROS, -NRNS1C (＝O) RCS, -CN, -C (＝O) OROS, -C (＝O) NRNS1RNS2, -OC (＝O) RCS, -C (＝O) RCS, and -NO2, wherein: Each RSS1is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl； Each RS2is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl； Each ROS is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl； Each RCS is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl； Each RNS1 and RNS2 are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl； When chemically making sense, one or two carbon of the said substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-8 cycloalkyl may be replaced by -O-, -N (RNS0) -, -S (＝O) 0-2-, -P (RPS) (＝O) -； Each RPS is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl； Each RNS0 is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, -CN, -OROS, -O (C (＝O) RCS) , -C (＝O) OROS) , -C (＝S) OROS) -O (C (＝S) RCS) -N (RNS1) (RNS2) , -N (RNS1) (S (＝O) 1-2RSS2) , -N (RNS1) (S (＝O) 1-2NRNS1RNS2) , -N (RNS1) (C (＝O) RCS) , -N (RNS1) (C (＝O) NRNS1RNS2) , -N (RNS1) (C (＝S) RCS) , -N (RNS1) (C (＝S) NRNS1RNS2) , -S (＝O) 1-2RSS2, -S (＝O) 1-2NRNS1RNS2, or -C (＝O) NRNS1RNS2, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl； when exist as a pair, RNS1 and RNS2, RNS1 and RSS2, or RNS1 and RCS may join together to form a 3-8 membered ring system；
  • As also used herein, the terms "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.
  • The term "alkoxy" as used herein refers to a hydrocarbon group connected through an oxygen atom, e.g., -O-ROS, wherein the hydrocarbon portion RO 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. For example, suitable alkoxy groups include methoxy, ethoxy, propyloxy, isopropoxy, methoxyethoxy, benzyloxy, allyloxy, and the like. Similarly, the term "alkylthio" refers to alkylsulfides of the general formula -S-RSS1, wherein the hydrocarbon portion RSS1 is as described for alkoxy groups. For example, contemplated alkylthio groups include methylthio, ethylthio, isopropylthio, methoxyethylthio, benzylthio, allylthio, and the like.
  • The term 'a mino' as used herein refers to the group -NH2. The term "alkylamino" refers to amino groups where one or both hydrogen atoms are replaced by a hydrocarbon group to form N (RNS1) (RNS2) as described above, wherein the amino nitrogen "N" can be substituted by one RNS group (referred as RNS1, as described and defined as above) or two RNS groups (referred as RNS1 and RNS2, as described and defined as above) . Exemplary alkylamino groups include methylamino, dimethylamino, ethylamino, diethylamino, etc. Also, the term "substituted amino" refers to amino groups where one or both hydrogen atoms are replaced by a hydrocarbon group RNS as described above, wherein the amino nitrogen "N" can be substituted by one or two RNS groups as described above.
  • The term 'acyl' as used herein refers to a group of the formula -C (＝O) -D, where D represents an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle as described above. Typical examples are groups wherein D is a C1-10 alkyl, C2-10 alkenyl or alkynyl, or phenyl, each of which is optionally substituted. In some embodiments, D can be H, Me, Et, isopropyl, propyl, butyl, C1-4 alkyl substituted with -OH, -OMe, or NH2, phenyl, halophenyl, alkylphenyl, and the like.
  • The term "aryloxy" as used herein refers to an aryl group connecting to an oxygen atom, wherein the aryl group may be further substituted. For example suitable aryloxy groups include phenyloxy, etc. Similarly, the term "arylthio" as used herein refers to an aryl group connecting to a sulfur atom, wherein the aryl group may be further substituted. For example suitable arylthio groups include phenylthio, etc.
  • The hydrocarbon portion of each alkoxy, alkylthio, alkylamino, and aryloxy, etc. can be substituted as appropriate for the relevant hydrocarbon moiety.
  • The term "halogen" as used herein 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.
  • The term "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. Examples of such groups include, without limitation, fluoroalkyl groups, such as fluoroethyl, trifluoromethyl, difluoromethyl, trifluoroethyl and the like.
  • The term "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.
  • The term "sulfonyl" refers to the group SO2-alkyl, SO2-substituted alkyl, SO2-alkenyl, SO2-substituted alkenyl, SO2-cycloalkyl, SO2-substituted cycloalkyl, SO2-cycloalkenyl, SO2-substituted cycloalkenyl, SO2-aryl, SO2-substituted aryl, SO2-heteroaryl, SO2-substituted heteroaryl, SO2-heterocyclic, and SO2-substituted heterocyclic, wherein each alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Sulfonyl includes, by way of example, methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.
  • The term "sulfonylamino" refers to the group -NRNS1SO2RNS2, wherein RNS1 and RNS2 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 RNS1 and RNS2 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, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein
  • The term "aminosulfonyl" refers to the group -SO2NRNS1RNS2, wherein each RNS1 and RNS2 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 RNS1 and RNS2 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, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, which are as defined herein.
  • The term "acylamino" refers to the groups -NRNS1C (＝O) alkyl, -NRNS1C (＝O) substituted alkyl, -NRNS1C (＝O) cycloalkyl, -NRNS1C (＝O) substituted cycloalkyl, -NRNS1C (＝O) cycloalkenyl, -NRNS1C (＝O) substituted cycloalkenyl, -NRNS1C (＝O) alkenyl, -NRNS1C (＝O) substituted alkenyl, -NRNS1C (＝O) alkynyl, -NRNS1C (＝O) substituted alkynyl, -NRNS1C (＝O) aryl, -NRNS1C (＝O) substituted aryl, -NRNS1C (＝O) heteroaryl, -NRNS1C (＝O) substituted heteroaryl, -NRNS1C (＝O) heterocyclic, and -NRNS1C (O) substituted heterocyclic, Each RNS1is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, aryl, fused aryl, heteroaryl, fused heterocycle, a C3-8 carbocyclic ring or a C4-8 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；
  • The term "alkoxycarbonyl amino" refers to the group -NRNS1C (＝O) ORNS2, wherein ach RNS1 and RNS2 are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-8 alkynyl, aryl, fused aryl, heteroaryl, fused heterocycle, a C3-8 carbocyclic ring or a C4-8 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 RNS1 and RNS2 may join together to form a 4, 5, 6 or 7-membered heterocyclic ring, when suitable, a carbon atom in the ring can be replaced by a heteroatom selected from N, S, O, and P
  • The term "aminocarbonylamino" refers to the group -NRNS1C (＝O) NRNS1RNS2, Each RNS1 and RNS2 are independently selected from hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, aryl, fused aryl, heteroaryl, fused heterocycle, a C3-8 carbocyclic ring or a C4-8 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 RNS1 and RNS2 may join together to form a 4, 5, 6 or 7-membered heterocyclic ring, when suitable, a carbon atom in the ring can be replaced by a heteroatom selected from N, S, O, and P.
  • It should further be recognized that 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, C1-4 alkyl, halo, or C1-4 haloalkyl. For example, a hydrogen atom in an alkyl or aryl can be replaced by an amino, halo or C1-4 haloalkyl or alkyl group.
  • The term "substituted" as used herein refers to a replacement of a hydrogen atom of the unsubstituted group with a functional group, and particularly contemplated functional groups include nucleophilic groups {e.g., -NH2, -OH, -SH, -CN, etc. ) , electrophilic groups (e.g., C (＝O) OR, C (＝X) OH, etc. ) , polar groups (e.g., -OH) , non-polar groups (e.g., heterocycle, aryl, alkyl, alkenyl, alkynyl, etc. ) , ionic groups (e.g., -NH3 +) , and halogens (e.g., -F, -Cl, -Br, -I) , NHCOR, NHCONH2, OCH2COOH, OCH2CONH2, OCH2CONHR, NHCH2COOH, NHCH2CONH2, NHSO2R, OCH2-heterocycles, -PO3H, -SO3H, amino acids, and all chemically reasonable combinations thereof. Moreover, the term "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.
  • In addition to the disclosure herein, in a certain embodiment, a group that is substituted has 1 , 2, 3, or 4 substituents, 1 , 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.
  • It is understood that in all substituted groups defined above, compounds arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further substituted by a substituted aryl group, etc. ) are not intended for inclusion herein. In such cases, the maximum number of such substitutions is three. For example, serial substitutions of substituted aryl groups specifically contemplated herein are limited to substituted aryl- (substituted aryl) -substituted aryl.
  • Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl) - (alkyl) -O-C (O) -.
  • As to 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. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.
  • The term "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.
  • As used herein, 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. Other pharmaceutically acceptable 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, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+ (C1-5alkyl) 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.
  • The term "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. Where applicable, 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. By way of example, 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. 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.
  • As described in detail herein, infra, provided compounds are selective inhibitors of tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1.
  • In certain embodiments, 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.
  • As used herein, the term "selectively inhibits, " as used in comparison to inhibition of kinase selected from ErbBl, ErbB2, ErbB4, TEC, BTK, ITK, BMX, JAK3, ALK, or RLK.
  • In some embodiments, the at least one kinase is tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1.
  • Notwithstanding, in certain embodiments, provided compounds do not appreciably inhibit, either reversibly or irreversibly, other protein kinases. In some embodiments, 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.
  • Synthesis and Intermediates
  • In certain embodiments, 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.
  • Provided in Scheme 1 is a general method for preparation of intermediate IN-1. By treatment of a certain carboxylic acid such as SM-C, with reagents such as SOCl2, POCl3, ClC (＝O) C (＝O) Cl, PCl5, and other reagents known to perform the same transformation in a suitable solvent such as DCM, 1, 2-dichloroethane, chloroform, toluene, benzene, chlorobenzene, dipropyl ether, diethyl ether, and others known suitable for the transformation, 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.
  • Provided in Scheme 2 is a general method for preparation of intermediate IN-2. Depending on the choice of Z, X3, and X4, IN-1 can selectively react with an amine derivative selected from Table 2 under suitable conditions such as heating in the presence of absence of a base, with or without a transition metal complex as a catalyst, to covert the C-X4 bond to C-R4； wherein Each -R4 is selected from a moiety described in Table 1. In a similar way, 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-X4 bond and formed the C-R4 bond when catalyzed by suitable transition metal complex； Each -R4 is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl.
  • Table 2
  • When chemically making sense, the carbon-hydrogen bonds in the moieties listed in the above Table 1 can be replaced with one to three carbon-R groups, wherein each -R is selected from -F,  substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl；
  • Provided in Scheme 3 is a general method for preparation of intermediate IN-3. Depending on the choice of Z, X3, and X4, 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-X3 bond and formed the C-R3 bondwhen catalyzed by suitable transition metal complex； Each -R3 is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl.
  • Provided in Scheme 4 is a general method for preparation of the compound of formula (I) . IN-3 can react with an amine derivative described in Table 2 under suitable conditions such as heating in the presence of absence of a base, with or without a transition metal complex as a catalyst, to covert the C-X4 bond to C-R4； wherein Each -R4 is selected from a moiety described in Table 1. In a similar way, 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-X4 bond and formed the C-R4 bond when catalyzed by suitable transition metal complex； Each -R4 is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl. When necessary, further reaction need to be performed to remove protective group (s) carried by R3 and/or R4 to convert the coupling product into the final compound of formula (I) . Occasionally, some chemical transformations can be applied to a compound of formula (I) obtained as described above and then convert it to another compound of formula (I) . It is possible to apply such transformation to the protected coupling product and then to perform the deprotection step later to afford the desired compound of formula (I) .
  • Provided in Scheme 5 is an alternative general method for preparation of the compound of formula (I) from 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-X3 bond and formed the C-R3 bond； Each -R3 is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl. When necessary, further reaction need to be performed to remove protective group (s) carried by R3 and/or R4 to convert the coupling product into the final compound of formula (I) . Occasionally, some chemical transformations can be applied to a compound of formula (I) and then convert it to another compound of formula (I) . It is possible to apply such transformation to the protected coupling product and then to perform the deprotection step later to afford the desired compound of formula (I) .
  • Uses, Formulation and Administration
  • Pharmaceutically Acceptable Compositions
  • 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. Examples of 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.
  • According to another embodiment, 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) .
  • In certain embodiments, 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) .
  • In certain embodiments, 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. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.
  • In certain embodiments, 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. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.
  • The term "patient" , as used herein, means an animal, preferably a mammal, and most preferably a human.
  • The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" 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 polymers, polyethylene glycol and wool fat.
  • Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • For this purpose, 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.
  • Pharmaceutically acceptable 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. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When 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.
  • Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These 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. Such materials include cocoa butter, beeswax and polyethylene glycols.
  • Pharmaceutically acceptable 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.
  • For topical applications, provided pharmaceutically acceptable 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. Alternatively, 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.
  • For ophthalmic use, provided pharmaceutically acceptable 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. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-
  • known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • In certain embodiments, pharmaceutically acceptable compositions of this invention are formulated for oral administration.
  • The amount of compounds 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. Preferably, 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.
  • It should also be understood that 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.
  • In one aspect, compounds of Formula (I) may inhibit tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular 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 colitis.
  • In accordance with the foregoing, the present invention provides:
  • (1) 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；
  • (2) a pharmaceutical 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；
  • (3) a method for the treatment of any particular indication set forth hereinbefore in a subject in need thereof which comprises administering an effective amount of a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same；
  • Further, 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；
  • (4) use of 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；
  • (5) a combination comprising 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；
  • (6) use of 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 which responds to inhibition of the anaplastic lymphoma kinase；
  • preferably, the disease to be treated is selected from anaplastic large cell lymphoma, non-Hodgkin's lymphomas, inflammatory myofibroblastic tumors, neuroblastomas and neoplastic diseases；
  • (7) a method for the treatment of a disease which responds to inhibition of the anaplastic lymphoma kinase, especially a disease selected from anaplastic large-cell lymphoma, non Hodgkin's lymphomas, inflammatory myofibroblastic tumors, neuroblastomas and neoplastic diseases, comprising administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • 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.
  • As used herein, the terms "treatment, " "treat, " and "treating" refer 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. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, 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.
  • Accordingly, 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. Specifically, 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.
  • In some embodiments, the present invention provides a method for treating or lessening the severity of one or more disorders selected from a cancer. In some embodiments, the cancer is associated with a solid tumor. In certain embodiments, the cancer is breast cancer, glioblastoma, lung cancer, cancer of the head and neck, colorectal cancer, bladder cancer, or non-small cell lung cancer. In some embodiments, 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..
  • In certain embodiments, 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.
  • 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. The expression "dosage unit form" as used herein 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. The term "patient" , as used herein, means an animal, preferably a mammal, and most preferably a human.
  • Pharmaceutically acceptable 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. In certain embodiments, 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. In addition to the active compounds, 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. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Injectable preparations, for example, 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. Among the acceptable vehicles and solvents that may be employed are water,  Ringer's solution, U. S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, 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.
  • In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other 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.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, 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 monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
  • 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. In some embodiments, 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. In such solid dosage forms 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. In the case of capsules, tablets and pills, 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. Examples of embedding compositions that can be used 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. Additionally, 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.
  • Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, 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. "
  • For example, compounds of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with chemotherapeutic agents to treat proliferative diseases and cancer. Examples of known 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, teniposide, amphotericin, alkylating agents (e.g., chlorambucil) , 5 -fluorouracil, campthothecin, cisplatin, metronidazole, and GleevecTM, among others. In other embodiments, a compound of the present invention is administered in combination with a biologic agent, such as Avastin or VECTIBIX.
  • In certain embodiments, compounds of the present invention, or a pharmaceutically acceptable composition thereof, 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, dexrazoxane, docetaxel, doxorubicin (neutral) , doxorubicin hydrochloride, dromostanolone propionate, epirubicin, epoetin alfa, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate, or zoledronic acid.
  • Other examples of agents the inhibitors of this invention may also be combined with include, without limitation: treatments for Alzheimer's Disease such as donepezil hydrochlorideand rivastigminetreatments 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 acetateand mitoxantrone； treatments for asthma such as albuterol and montelukastagents 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 cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine； neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents； agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins； agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents； agents for treating blood disorders such as corticosteroids, antileukemic agents, and growth factors； and agents for treating immunodeficiency disorders such as gamma globulin.
  • In certain embodiments, compounds of the present invention, or a pharmaceutically acceptable composition thereof, 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. Alternatively, 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.
  • As used herein, the term "combination, " "combined, " and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, 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. Accordingly, 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.
  • The amount of both, an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) ) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, 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.
  • In those 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 μg/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. Preferably 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. Vascular stents, for example, have been used to overcome restenosis (re -narrowing of the vessel wall after injury) . However, 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.
  • DESCRIPTION OF EXEMPLARY EMBODIMENTS
  • As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
  • General Procedure: The LCMS conditions for sample characterization was as followed: Column: Agilent Zorbax Eclipse XDB-C18, 4.6 mm x 30 mm, 3.5 um； Temperature : 25 ℃； Eluent A : H2O + 0.1％TFA； Eluent B: Acetonitrile + 0.1％TFA； Flow Rate: 2.0 mL/min； Gradient: the gradient start (0 min) with 5％ Eluent B and gradually increase to 100％of Eluent B over 2.30 min (2.30 min run) , then the gradient was kept at 100％of Eluent B for 1.30 min and the run was ended (total run 4.00 min) .
  • Section 1.1: The synthesis of Intermediates IN-1
  • IN-1-01: 5-bromo-6-chloro-N- (4- (trifluoromethoxy) phenyl) nicotinamide
  • A stirred solution of 5-bromo-6-chloro-nicotinic acid (4 g, 16.92 mmol) and DMF (0.39 mL) in toluene (35 mL) was treated dropwise with SOCl2 (3.68 mL, 50.75 mmol) at RT and then stirred at 85℃ for 2.5 h. The solvent was evaporated off under reduced pressure and the residue was redissolved in DCM (20 mL) , and the mixture was cooled in an icy water bath and to this solution a mixture of 4- (trifluoromethoxy) aniline (3.18 g) and DIPEA (8.84 mL) in DCM (15 mL) was added dropwise. The mixture was stirred at rt for 1 hr. Then a saturated aqueous solution of NaHCO3 was added and the mixture was stirred at rt for 10 min and a solid was formed. The mixture was then diluted with 35 mL of hexane and filtered to collect the white solid, washed with more water and air dried to afford the desired (5.40 g, 84％yield) . (Rt ＝ 2.27 min, +ESI m/z: MH+ ＝ 394.0)
  • IN-1-02: 5-bromo-6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) nicotinamide
  • The title compound was synthesized in 89％yield according to procedure described above for IN-1-01 by using 4- (chlorodifluoromethoxy) aniline to replace 4- (trifluoromethoxy) aniline. (Rt ＝ 2.34 min, +ESI m/z: MH+ ＝ 487.0)
  • IN-1-03: 6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -5-iodonicotinamide
  • A stirred solution of 6-hydroxy-5-iodonicotinic acid (40 g) and DMF (3.51 mL) in toluene (315 mL) was treated dropwise with SOCl2 (43.9 mL) at RT and then stirred at 85℃ for 2.5 h. The solvent was evaporated off under reduced pressure and the residue was redissolved in DCM (315 mL) . The solution was cooled in an icy water bath and to this solution a mixture of 4- (chlorodifluoromethoxy) aniline (26 . 3 g) and Et3N (63 mL) in DCM (315 mL) was added dropwise. The mixture was stirred at rt for 1 hr. Then a saturated aqueous solution of NaHCO3 was added and the mixture was stirred at rt for 10 min and a solid was formed. The mixture was then diluted with 315 mL of hexane and filtered to collect the white solid, washed with more water and air dried to afford 6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -5-iodonicotinamide (55.97 g) . (Rt ＝ 2.28 min, +ESI m/z: MH+ ＝ 459.0) .
  • IN-1-04: 4-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -3-iodobenzamide
  • The title compound was synthesized in 98％yield according to procedure described above for IN-1-01. (Rt ＝ 2.49 min, +ESI m/z: MH+ ＝ 501.9/504.0) .
  • IN-1-05: 5-bromo-6-iodo-N- (4- (trifluoromethoxy) phenyl) nicotinamide
  • To a solution of IN-1-01 (15g, 39.92 mmol) in MeCN (300 mL) , under N2 atmosphere, TMSCl (5.1 mL, 39.85 mmol) was added, followed by NaI (22.75 g, 151.79 mmol) . Immediately, the light brown solution becomes an orange suspension. The mixture was stirred at room temperature for 1h. Then, the mixture was poured into water (100 mL) and saturated solution of Na2SO3 (100 mL) and the formed suspension was stirred for 30 min. The solid was isolated by filtration and dried at 50℃, affording the product as a light yellow solid (18.39, 99％) . (Rt ＝ 2.34 min, +ESI m/z: MH+ ＝ 487.0)
  • IN-1-06: 5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6-iodonicotinamide
  • The title compound was prepared as it was described for the synthesis of IN-1-05 by using IN-1-02 (1.6 g, 3.88 mmol) , TMSCl (0.52 mL, 4.08 mmol) , NaI (2.32 g, 15.52 mmol) with MeCN (30 mL) as a solvent. The product was obtained as a yellow solid (1.47g, 75％) after purification by flash chromatography (0-40％Hexanes-EtOAc) . (Rt ＝ 2.54 min, +ESI m/z: MH+ ＝ 503.0) .
  • Section 1.2: The synthesis of intermediates IN-2
  • IN-2-01: 5-bromo-6- (1-imino-1-oxidothiomorpholino) -N- (4- (trifluoromethoxy) phenyl) nicotinamide
  • A mixture of IN-1-01 (0.6g, 1.52 mmol) , 1-iminothiomorpholine 1-oxide (0.31 g, 2.28 mmol) and N (i-Pr) 2Et (0.52mL, 3.04 mmol) in i-PrOH (10 mL) was heated at 125 ℃ for 72 h. The solvent was evaporated and the residue was purified by flash chromatography (0-100 ％solvent B/hexanes, while solvent B is a solvent mixture of EtOAc/MeOH＝90/10) and the product was obtained as a yellowish solid (0.14g, 19％) . LC/MS (Rt ＝ 1.78 min, +ESI m/z: MH+ ＝ 493.1) .
  • IN-2-02:
  • 5-bromo-6- ( (S) -3- (S-methylsulfonimidoyl) pyrrolidin-1-yl) -N- (4- (trifluoromethoxy) phenyl) nicotinamide
  • Following the procedure for the synthesis of IN-2-01 under conditions present above, IN-2-02 was synthesized. LC/MS (Rt ＝ 1.79 min, +ESI m/z: MH+ ＝ 507.1) .
  • IN-2-03:
  • 5-bromo-6- ( (3R) -3- (S-methylsulfonimidoyl) pyrrolidin-1-yl) -N- (4- (trifluoromethoxy) phenyl) nicotinamide
  • Following the procedure for the synthesis of IN-2-01 under conditions present above, IN-2-03 was synthesized. LC/MS (Rt ＝ 1.79 min, +ESI m/z: MH+ ＝ 507.1) .
  • IN-2-04:
  • 5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- ( (3S) -3- (S-methylsulfonimidoyl) pyrrolidin-1-yl) nicotin amide
  • Following the procedure for the synthesis of IN-2-01 under conditions present above, IN-2-04 was synthesized. LC/MS (Rt ＝ 1.83 min, +ESI m/z: MH+ ＝ 523.1) .
  • IN-2-05:
  • 5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- ( (3R) -3- (S-methylsulfonimidoyl) pyrrolidin-1-yl) nicotin
  • Following the procedure for the synthesis of IN-2-01 under conditions present above, IN-2-05 was synthesized. LC/MS (Rt ＝ 1.83 min, +ESI m/z: MH+ ＝ 523.1) .
  • IN-2-06:
  • (S) -5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (3- (methylsulfonyl) pyrrolidin-1-yl) nicotinamide
  • Following the procedure for the synthesis of IN-2-01 under conditions present above, IN-2-06 was synthesized； Flash chromatography: (0-100 ％EtOAc/hexanes) . LC/MS (Rt ＝ 2.12 min, +ESI m/z: MH+ ＝ 524.0) .
  • IN-2-07:
  • (R) -5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (3- (methylsulfonyl) pyrrolidin-1-yl) nicotinamide
  • Following the procedure for the synthesis of IN-2-01 under conditions present above, IN-2-07 was synthesized； Flash chromatography: (0-100 ％EtOAc/hexanes, ) . LC/MS (Rt ＝ 2.12 min, +ESI m/z: MH+ ＝ 524.0) .
  • IN-2-08:
  • 5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) nicotin amide
  • To a round-bottom flask was charged with IN-1-02 (0.80g, 1.59 mmol) , 1- (tetrahydro-2H-pyran-2-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.57g, 2.07 mmol) , K3PO4 (1.01 g, 4.77 mmol) , and [Pd (PPh3) 4] (0.091g, 0.08 mmol) . Then, a condenser was attached and the system was put under vacuum, and toluene was added (30 mL) via syringe while under vacuum. The system was put under N2 atmosphere with a balloon filled with N2 and the reaction was heated at reflux overnight. The reaction was filtered and the solvent was removed in vacuo and the residue was purified by flash chromatography (0-100％10 CV, Hexanes-EtOAc) to afford the title compound (0.65 g, 78％) . LC/MS (Rt ＝ 2.34 min, +ESI m/z: MH+ ＝ 527.0) .
  • IN-2-09: 5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (1H-pyrazol-5-yl) nicotinamide
  • A solution of IN-2-08 (0.53 g, 1 mmol) in 80％aqueous solution of AcOH (30 mL) was heated at 100℃ overnight. After cooling down, the solvent was removed in vacuo, and to the residue saturated NaHCO3 solution was added (30 mL) and followed by EtOAc (30 mL) . The organic phase was separated and washed once again with saturated NaHCO3 (30 mL) , dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography (0-100％hexanes-EtOAc) to afford the title compound as a light yellow solid (0.28g, 63％) . LC/MS (Rt ＝ 2.04 min, +ESI m/z: MH+ ＝ 443.1) .
  • IN-2-10: 5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (1-methyl-1H-pyrazol-3-yl) nicotinamide
  • To a solution of IN-2-09 (0.28 g, 0.63 mmol) in anhydrous DMF (10 mL) stirred in an ice/water bath, NaH (1.38 mmol) was added portionwise. The reaction was stirred at room temperature for 1 h and then, MeI (43μL, 0.69 mmol) was added. The reaction was stirred at room temperature overnight. After cooling down, the mixture was quenched with water (30 mL) and the mixture was extracted with EtOAc (3x30 mL) . The combined organic layers were washed with water (3x100 mL) , dried over Na2SO4 and the solvent was removed in vacuo. The purification was carried out by flash chromatography (0-100％hexanes-EtOAc) and the title compound was obtained as a yellow solid (0.1443 g, 50 ％) . LC/MS (Rt ＝ 2.06 min, +ESI m/z: MH+ ＝ 457.2) .
  • IN-2-11: 5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6-hydrazinylnicotinamide
  • To a mixture of IN-1-02 (7.5 g, 18.20 mmol) in i-PrOH (100 mL) stirred at rt in a sealed tube, 14 mL of hydrazine monohydrate was added dropwise. After the addition, the tube was sealed and the mixture was heated to 125 ℃ and stirred at this temperature overnight. The mixture was cooled down to rt and 100 mL of water was added. The precipitate thus formed was collected by filtration and washed with water, air dried to afford the title compound as a white solid (7.42 g, 100％yield) used directly in next step. LC/MS (Rt ＝ 1.62 min, +ESI m/z: MH+ ＝ 407.0/409.0) .
  • IN-2-12: 5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-methyl-1H-pyrazol-1-yl) nicotinamide and
  • IN-2-13: 5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (5-methyl-1H-pyrazol-1-yl) nicotinamide
  • A mixture of IN-2-11 (2.4 g, 5.89 mmol) and (E) -4- (dimethylamino) but-3-en-2-one (0.80 g, 7.07 mmol) in 2-PrOH (29 mL) in a sealed tube was stirred at 100℃ overnight. LCMS showed that around 25％conversion. The reaction was continued for 24 hr more and observed around 44％conversion. Thus 1 mL of AcOH was added to the reaction mixture and heated at 100℃ for 3 hr. LCMS showed the completed consumption of SM. The reaction was worked up by addition of NaHCO3/H2O (sat) and extracted with EtOAc, dried over Na2SO4, filtered, and evaporated. The residue was purified by flash chromatography (0-70％EtOAc/hexanes) to title compounds. IN-2-12 was obtained (1.9 g) not very pure thus swished with TBME afforded 0.41 g in pure form. LC/MS (Rt ＝ 2.24 min, +ESI m/z: MH+ ＝ 457.0/459.0) . IN-2-12 was obtained as pure from flash chromatography (0.44 g) . LC/MS (Rt ＝ 2.16 min, +ESI m/z: MH+ ＝ 457.0/459.0) .
  • Section 1.3: The synthesis of intermediates IN-3
  • IN-3-01: 2-chloro-N- (4- (chlorodifluoromethoxy) phenyl) - [3, 3'-bipyridine] -5-carboxamide (LL-04195)
  • 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) , K3PO4 (3.61, 17 mmol) , and [Pd (dppf) Cl2] . CH2Cl2 (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 N2 atmosphere with a nitrogen balloon. The reaction was heated at reflux (85℃) for 12 h. The mixture was diluted with water (150 mL) and transferred to a separation funnel, extracted with EtOAc (3x200 mL) . The organic layers were combined and dried over Na2SO4, filtered, and evaporated. The residue was purified by flash chromatography (0-100％EtOAc/hexanes) to afford the title compound as a brown solid (4.43g, 89％) . LC/MS (Rt ＝ 1.71 min, +ESI m/z: MH+ ＝ 410.2) .
  • Method 2: A mixture of IN-1-03 (40.0 g, 87.14 mmol) , pyridin-3-ylboronic acid (12.85 g, 104.57 mmol) , K2CO3 (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. A nitrogen atmosphere was established to the system by a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and the organic layer was separated, and dried over Na2SO4, filtered and evaporated. The residue was purified by recrystallization from toluene to afford the desired (24.70 g) .
  • IN-3-02: 6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -5- (pyrimidin-5-yl) nicotinamide
  • The title compound was synthesized by following the procedure described above for the synthesis of IN-3-01 (Method 2) from pyrimidin-5-ylboronic acid to afford the title compound 1.35g, 30％yield) . (Rt ＝ 1.81 min, +ESI m/z: MH+ ＝ 411.0/413.0) .
  • IN-3-03:
  • 6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -5- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) nicotina mide
  • A round-bottom flask was charged with IN-1-03 (0.80g, 1.74 mmol) , 1- (tetrahydro-2H-pyran-2-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.63 g, 2.26 mmol) , K3PO4 (1.11 g, 5.22 mmol) , and [Pd (PPh3) 4] (0.10g, 0.09 mmol) . Then, a condenser was attached and the system was put under vacuum and toluene was added (30 mL) via syringe under vacuum. Then, the system was put under a N2 atmosphere and the reaction was heated at reflux overnight. After cooling down to room temperature, the mixture was diluted with water (25 mL) and extracted with EtOAc (3x25mL) . The combined organic layers were dried over Na2SO4 and then the solvent was removed in vacuo. The residue was purified by flash chromatography (0-100％EtOAc/Hexanes) to afford the title compound as a light yellow solid (0.78 g, 93％) . (Rt ＝ 2.19 min, +ESI m/z: MH+ ＝ 483.2) .
  • IN-3-04: 6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -5- (1-methyl-1H-pyrazol-4-yl) nicotinamide
  • To a reaction vial equipped with a septum cap was charged with IN-1-03 (0.68g, 1.63 mmol) , 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.408 g, 1.96 mmol) , K3PO4 (1.04 g, 4.90 mmol) , and [Pd (PPh3) 4] (94 mg, 0.08 mmol) under the vacuum, toluene (16 mL) was added via a syringe and then a N2 balloon was applied. The mixture was heated to 110 ℃ overnight. The mixture was cooled down to rt and added to a separation funnel with water. The vial was washed with EtOAc and added to the separation funnel. The organic phase was separated, dried over Na2SO4, filtered and evaporated onto 6 g of silica gel. The sample was dry loaded onto silica gel column and purified by flash chromatography (0-100％EtOAc/Hexanes) to afford the title compound as a white solid (0.23 g, 34％yield) . (Rt ＝ 1.99 min, +ESI m/z: MH+ ＝ 458.9) .
  • IN-3-05: 4-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -3- (pyridin-3-yl) benzamide
  • A mixture of IN-1-04 (4.0 g, 7.96 mmol) , pyridin-3-ylboronic acid (1.17 g, 9.55 mmol) , K2CO3 (2.20 g) , Tetrakis (triphenylphosphine) palladium (0) (0.46 g, 0.4 mmol) was charged in a flask and then a mixture of 40 mL of 1, 4-dioxane/H2O (4/1) 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. A nitrogen atmosphere was established to the system by a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and the organic layer was separated, and dried over Na2SO4, filtered and evaporated. The sample was dry loaded onto silica gel column and purified by flash chromatography (0-100％EtOAc/Hexanes) to afford the title compound as a white solid (3.15 g, 87％yield) . LC/MS (Rt ＝ 1.78 min, +ESI m/z: MH+ ＝ 453.0/455.0) .
  • IN-3-06: 2-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -6'-fluoro- [3, 3'-bipyridine] -5-carboxamide
  • A mixture of IN-1-03 (2.0 g, 4.36 mmol) , (6-fluoropyridin-3-yl) boronic acid (0, 74 g, 5.23 mmol) , K2CO3 (1.20 g) , Tetrakis (triphenylphosphine) palladium (0) (0.25 g, 0.22 mmol) was charged in a flask and then a mixture of 40 mL of 1, 4-dioxane/H2O (4/1) 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. A nitrogen atmosphere was established to the system by a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and the organic layer was separated, and dried over Na2SO4, filtered and evaporated. The sample was dry loaded onto silica gel column and purified by flash chromatography (0-100％EtOAc/Hexanes) to afford the title compound as a white solid (1.57 g, 84％ yield) . LC/MS (Rt ＝ 2.02 min, +ESI m/z: MH+ ＝ 428.0) .
  • IN-3-07: 2-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -2'-fluoro- [3, 3'-bipyridine] -5-carboxamide
  • A mixture of IN-1-03 (4.0 g, 8.71 mmol) , (2-fluoropyridin-3-yl) boronic acid (1.84 g, 13.07 mmol) , K2CO3 (3.61 g) , Tetrakis (triphenylphosphine) palladium (0) (0.50 g, 0.44 mmol) was charged in a flask and then a mixture of 65 mL of 1, 4-dioxane/H2O (4/1) 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. A nitrogen atmosphere was established to the system by a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and the organic layer was separated, and dried over Na2SO4, filtered and evaporated. The sample was dry loaded onto silica gel column and purified by flash chromatography (0-60％EtOAc/Hexanes) to afford the title compound as a yellow gum (3.81 g, 60％ purity based on LCME, 61％yield) . LC/MS (Rt ＝ 1.99 min, +ESI m/z: MH+ ＝ 428.0) . The sample was used directly in next step without further purification.
  • IN-3-08: 6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -5- (1H-pyrazol-5-yl) nicotinamide
  • A round-bottom flask was charged with IN-3-03 (3.56 g, 7.37 mmol) in 210 mL of a solvent mixture (MeOH/THF/H2O ＝ 5/5/1 ratio) , 2 mL of con H3PO4 was added and the mixture was heated at reflux for 4 hr. The solvent was removed by evaporation and the residue was diluted with water, Neutralized sat NaHCO3/water. The solid was filtered off, washed with water, air-dried to afford the title compound as a white solid (2.3 g) . (Rt ＝ 1.75 min, +ESI m/z: MH+ ＝ 399.0) .
  • Section 1.4: The synthesis of intermediates AM
  • AM-01: (3S) -3- (S-methylsulfonimidoyl) pyrrolidine
  • The title compound was synthesized according to Scheme AM-01.
  • Step 1: (R) -benzyl 3-hydroxypyrrolidine-1-carboxylate
  • To a solution of (R) -pyrrolidin-3-ol (10 g, 114.8 mmol) and NEt3 (18.3 mL, 131.2 mmol) in CH2Cl2 (120 mL) under N2 atmosphere stirred in an ice/water bath, was added Cbz-Cl (15.6mL, 109.31 mmol) dropwise. The reaction was stirred in the ice/water bath for 2 h. The reaction was worked up by the addition of CH2Cl2 (25 mL) , and 1N aqueous solution of HCl (100 mL) . The organic phase was separtated, washed with saturated aqueous solution of NaHCO3 (100 mL) , and brine (100 mL) , dried over Na2SO4 and the solvent was removed in vacuo. The yellowish residue was dissolved in EtOAc and filtered through a silica gel pad, washing with more EtOAc until no more product was washed out. The solvent was evaporated to afford a light yellowish oil as the title compound (20.19g, 83％) . LC/MS (Rt ＝ 1.49 min, +ESI m/z: MH+ ＝ 222.3) .
  • Step 2: (R) -benzyl 3- ( (methylsulfonyl) oxy) pyrrolidine-1-carboxylate
  • To a solution of (R) -benzyl 3-hydroxypyrrolidine-1-carboxylate (10 g, 45.2 mmol) , and NEt3 (18.9 mL, 135.6 mmol) in CH2Cl2 (200 mL) stirred at -15 ℃, MsCl (5.2 mL, 67.8 mmol) was added dropwise. The reaction mixture was stirred for 30 min at -15 ℃, and for 30 min at 0 ℃. The mixture was pour into a separation funnel, washed with saturated solution of NaHCO3 (2x60 mL) , and brine (60 mL) . The organic phase was dried over Na2SO4 and evaporated toafford the title compound as a yellow oil. (13.09g, 97％ yield) . LC/MS (Rt ＝ 1.74 min, +ESI m/z: MH+ ＝ 300.2) .
  • Step 3: (S) -benzyl 3- (methylthio) pyrrolidine-1-carboxylate
  • To solution of (R) -benzyl 3- ( (methylsulfonyl) oxy) pyrrolidine-1-carboxylate (5.84g, 19.51 mmol) in DMF (40 mL) was added stirred under a N2 atmosphere in an ice/water bath, an aqueous solution of NaSMe (21％, 9.8 mL, 29.3 mmol) was added dropwise. The reaction mixture was stirred in the ice/water bath for 1h and then at room temperature overnight. The reaction was worked up by the addition of water (50 mL), and extracted with EtOAc (3x100 mL) . The combined organic phase were evaporated to approximately one third of the volume and washed with water (4x50 mL) , dried over Na2SO4 and the evaporated. The residue was purified by flash chromatography (0-80％EtOAc/hexane) to afford the title compound d as a yellowish oil (4.90 g, 99％Yield) . LC/MS (Rt ＝ 1.98 min, +ESI m/z: MH+ ＝ 252.2) .
  • Step 4: (S) -benzyl 3- (S-methyl-N-tosylsulfinimidoyl) pyrrolidine-1-carboxylate
  • To a mixture of (S) -benzyl 3- (methylthio) pyrrolidine-1-carboxylate (4.90g, 19.50 mmol) , N (Bu) 4Br (0.63 g, 1.95 mmol) in CH2Cl2 (60 mL) stirred at rt, was added chloramine-T trihydrated (6.72 g, 23.89 mmol) portionwise. The mixture was stirred at rt for 6 h. The white solid was removed by filtration and the filtrate was evaporated to afford the title compound as a yellow oil (8.19g, 100％) . LC/MS (Rt ＝ 1.76 min, +ESI m/z: MH+ ＝ 421.2) .
  • Step 5: (3S) -benzyl 3- (S-methyl-N-tosylsulfonimidoyl) pyrrolidine-1-carboxylate
  • To a mixture of (S) -benzyl 3- (S-methyl-N-tosylsulfinimidoyl) pyrrolidine-1-carboxylate (8.19g, 19.47 mmol) and Bu4NBr (3.14 g, 9.73 mmol) in a 1/1 solvent mixture of EtOAc and CH2Cl2 (40 mL each) ,  NaClO aqueous solution (8.85％, 110 mL) were added and the reaction mixture was stirred at rt for 15h. TLC showed that (S) -benzyl 3- (S-methyl-N-tosylsulfinimidoyl) pyrrolidine-1-carboxylate was not completely consumed and thus more NaClO solution (30 mL) was added and the mixture was stirred at rt overnight. The mixture was poured into a separation funnel and the organic phase was separated. The aqueous phase was extracted with CH2Cl2 (100 mL) . The organic layers were combined, dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (0-100％ solvent B/hexanes, while solvent B is a 9/1 solvent mixture of EtAcO/MeOH) to afford the title compound as a colorless oil (3.94 g, 46％yield) . LC/MS (Rt ＝ 1.92 min, +ESI m/z: MH+ ＝ 437.2) .
  • Step 6: (3S) -3- (S-methylsulfonimidoyl) pyrrolidine
  • To a mixture of Na (0.83 g, 36.14 mmol) in anhydrous THF (50mL) stirred under N2 atmosphere at rt naphthalene (6.07g, 47.32 mmol) was added in one portion. The reaction was stirred at rt for 2 h and a dark green solution was obtained. The solution was cooled in an ice/water bath and (3S) -benzyl 3- (S-methyl-N-tosylsulfonimidoyl) pyrrolidine-1-carboxylate (3.94g, 9.03 mmol) in anhydrous THF (120 mL), was added dropwise. The reaction was stirred at this temperature for 1h and allowed to warm to room temperature, quenched by the addition of 3N aqueous solution of HCl (25 mL) . The mixture was washed with CH2Cl2 (3x25 mL) and the aqueous layer was evaporated. The residue was redissolved in water (25 mL) and made alkaline with saturated solution of NaHCO3. The resulting mixture was filtrated and the filtrate was evaporated. The residue was treated with EtOH (50 mL) and filtered to remove the salt. The filtrate was evaporated to afford the title compound as a brown gum (0.41g, 31％) , which was used directly in next step. LC/MS (Rt ＝ 0.30 min, +ESI m/z: MH+ ＝ 149.2) .
  • AM-02: (3R) -3- (S-methylsulfonimidoyl) pyrrolidine
  • The title compound was synthesized according to the procedure described above for the synthesis of AM-01 by using (S) -pyrrolidin-3-ol instead of (R) -pyrrolidin-3-ol as the starting material. LC/MS (Rt ＝ 0.30 min, +ESI m/z: MH+ ＝ 149.2) .
  • AM-03: (S) -3- (methylsulfonyl) pyrrolidine
  • The title compound was prepared according to Scheme AM-03.
  • Step 1: (S) -benzyl 3- (methylsulfonyl) pyrrolidine-1-carboxylate
  • The thioether (S) -benzyl 3- (methylthio) pyrrolidine-1-carboxylate (1.30 g, 5.17 mmol) was dissolved in MeOH (30 mL) and to this solution, Na2WO4.2H2O (0.51 g, 1.55 mmol) was added. The mixture was then cooled in an ice/water bath and at this temperature, H2O2 (30％in H2O, 1.2 mL, 10.34 mmol) was added dropwise. Then the reaction was stirred at 50 ℃ 1 hr. The reaction was cooled down to rt and quenched by the addition of saturated aqueous solution of Na2SO3 and a grain of KI. The mixture was stirred at room temperature for 30 min and then the solvent was evaporated. The residue was treated with EtOAc (30 mL) and water (30 mL) organic layer was separated, the aqueous phase was extracted with EtOAc (2x25 mL) . The organic phases were combined, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography (0-100％EtOAc/hexanes) to afford a white solid as the title compound (1.11g, 76％yield) . LC/MS (Rt ＝ 1.59 min, +ESI m/z: MH+ ＝ 284.2) .
  • Step 2: ( (S) -3- (methylsulfonyl) pyrrolidine
  • To a round-bottom flask containing containing (S) -benzyl 3- (methylsulfonyl) pyrrolidine-1-carboxylate (1.11g, 3.92 mmol) , Pd/C (10％, 0.33 g) under vacuum, MeOH was added (30 mL) via a cannula. Then a balloon filled with H2 was applied. The reaction was stirred at 50 ℃ for 48 h. After cooling down to room temperature, a vacuum was applied and filled back with N2. The mixture was filtered over celite , and the solvent was evaporated. The 1H NMR spectrum showed that the residue is a 1: 1 mixture the title compound and the starting material (50％yield) . This mixture was used directly in next step without further purification. LC/MS (Rt ＝ 0.25 min, +ESI m/z: MH+ ＝ 150.1) .
  • AM-04: (R) -3- (methylsulfonyl) pyrrolidine
  • The title compound was prepared according to Scheme AM-04 by using (R) -benzyl 3- (methylthio) pyrrolidine-1-carboxylate (1.17g , 4.13 mmol) as starting material and following the procedure described as above for the synthesis of AM-03. The 1H NMR spectrum showed that the residue is a 1.5: 1 mixture the title compound and the starting material (ca 60％yield) . This mixture was used directly in next step without further purification. LC/MS (Rt ＝ 0.25 min, +ESI m/z: MH+ ＝ 150.1) .
  • Section 2.1: The synthesis of Examples
  • Example 001:
  • N- (4- (chlorodifluoromethoxy) phenyl) -6- ( (3S) -3- (S-methylsulfonimidoyl) pyrrolidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide
  • To a round bottom flask containing 5-bromo-6- ( (S) -3- (S-methylsulfonimidoyl) pyrrolidin-1-yl) -N- (4- (trifluoromethoxy) phenyl) nicotinamide (0.196g, 0.37 mmol) , 1- (tetrahydro-2H-pyran-2-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.134 g, 0.48 mmol) , K3PO4 (0.2356g, 1.11 mmol) , and [Pd (PPh3) 4] (0.0214 g, 0.02 mmol) under vacuum, toluene (15mL) was added via syringe. A nitrogen balloon was applied and the mixture was heated at reflux overnight. The mixture was cooled down to rt and filtered through a celite pad, washed with EtOAc, and evaporated. The crude thus obtained was redissolved in 10 mL of 4/1 mixture acetic acid/H2O and the mixture was heated at reflux for 5 h. The solvent was evaporated and the residue was purified by flash chromatography (0-30％Solvent B/DCM, while solvent B is a 1/5 mixture of con ammonia/MeOH) to afford the desired (50 mg, 26％yield) . LC/MS (Rt ＝ 1.64 min, +ESI m/z: MH+ ＝ 511.2) .
  • Example 002:
  • N- (4- (chlorodifluoromethoxy) phenyl) -6- ( (3R) -3- (S-methylsulfonimidoyl) pyrrolidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide
  • 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) . LC/MS (Rt ＝ 1.64 min, +ESI m/z: MH+ ＝ 511.2) .
  • Example 003:
  • (S) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3- (methylsulfonyl) pyrrolidin-1-yl) -5- (1H-pyrazol-5-yl) nicot inamide
  • 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) . LC/MS (Rt ＝ 1.81 min, +ESI m/z: MH+ ＝ 512.1) .
  • Example 004:
  • (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3- (methylsulfonyl) pyrrolidin-1-yl) -5- (1H-pyrazol-5-yl) nicot inamide
  • 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) . LC/MS (Rt ＝ 1.81 min, +ESI m/z: MH+ ＝ 512.1) .
  • Example 005: N- (4- (chlorodifluoromethoxy) phenyl) -5, 6-di (1H-pyrazol-5-yl) nicotinamide
  • To a round bottom flask containing 5-bromo-6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) nicotinamide (0.20g, 0.49mmol) , 1- (tetrahydro-2H-pyran-2-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.41 g, 1.47 mmol) , K3PO4 (0.62 g, 2.94 mmol) , and [Pd (PPh3) 4] (85 mg, 0.07 mmol) under vacuum, toluene (15mL) was added via syringe. A nitrogen balloon was applied and the mixture was heated at reflux overnight. The mixture was cooled down to rt and filtered through a celite pad, washed with EtOAc, and evaporated. The crude thus obtained was redissolved in 10 mL of 4/1 mixture acetic acid/H2O and the mixture was heated at reflux for 48 h. The solvent was evaporated and the residue was purified by flash chromatography (0-30％Solvent B/DCM, while solvent B is a 1/5 mixture of con ammonia/MeOH) to afford the desired (122 mg, 55％yield) . LC/MS (Rt ＝ 1.74 min, +ESI m/z: MH+ ＝ 431.1) .
  • Example 006: N- (4- (chlorodifluoromethoxy) phenyl) - [3, 2': 3', 3” -terpyridine] -5'-carboxamide
  • To a round bottom flask charged with 5-bromo-6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) nicotinamide (0.15g, 0.36mmol) , pyridin-3-ylboronic acid (0.13 g, 1.08 mmol) , K3PO4 (0.23g, 1.08 mmol) , [Pd (dppf) Cl2] . CH2Cl2 (0.088 g, 0.11 mmol) under vacuum, 15 mL of a solvent mixture containing DME/H2O/EtOH (7/3/2) was added via syringe. The reaction was heated at reflux (85℃) overnight under nitrogen atmosphere. The reaction was cooled down to rt and and water was added. The mixture was extracted with EtOAc, dried over Na2SO4, evaporated and 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 as a light brown solid (0.101 g, 61 ％ yield) . LC/MS (Rt ＝ 1.54 min, +ESI m/z: MH+ ＝ 453.2) .
  • Example 007: N- (4- (chlorodifluoromethoxy) phenyl) - [4, 2': 3', 4” -terpyridine] -5'-carboxamide
  • The title compound was synthesized by following the procedure described above for the synthesis of Example 006 from pyridin-4-ylboronic acid to afford the title compound (0.126 g, 76％yield) . LC/MS (Rt ＝ 1.54 min, +ESI m/z: MH+ ＝ 453.2) .
  • Example 008: N- (4- (chlorodifluoromethoxy) phenyl) -5, 6-di (pyrimidin-5-yl) nicotinamide
  • The title compound was synthesized by following the procedure described above for the synthesis of Example 006 from pyrimidin-5-ylboronic acid to afford the title compound (0.157 g, 95％) . LC/MS (Rt ＝ 1.80 min, +ESI m/z: MH+ ＝ 455.3) .
  • Example 009: N- (4- (chlorodifluoromethoxy) phenyl) -5, 6-di (1H-pyrazol-4-yl) nicotinamide
  • The title compound was synthesized by following the procedure described above for the synthesis of Example 006 from 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole to afford the title compound (0.078 g, 51％) . LC/MS (Rt ＝ 1.87 min, +ESI m/z: MH+ ＝ 431.3) .
  • Example 010:
  • 5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (1-methyl-1H-pyrazol-3-yl) nicotinamide
  • 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) , K2CO3 (0.94 g, 0.68 mmol) , and [Pd (PPh3) 2Cl2] (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. Then, the system was put under N2 atmosphere and the reaction was heated at 120 ℃ overnight. After this time, the organic layer was saperated and the solvent was removed in vacuo. The residue (0.1566 g, 0.30 mmol) was redissolved in 80％aqueous solution of AcOH (10 mL) was heated at 100℃ overnight. After cooling down, the solvent was removed in vacuo, the residue was treated with saturated NaHCO3 solution (30 mL) and EtOAc (30 mL) . The organic phase was separated and washed once again with saturated NaHCO3 (30 mL), dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography (0-100％Solvent B/hexane, while solvent B is a solvent mixture of 10％MeOH in EtOAc) to afford a light yellow solid. The solid was triturated with TBME and t filtered to afford the title compound (0.0252 g, 19％) . LC/MS (Rt ＝ 1.72 min, +ESI m/z: MH+ ＝ 445.3) .
  • Example 011:
  • N- (4- (chlorodifluoromethoxy) phenyl) -3- (1H-pyrazol-5-yl) - [2, 3'-bipyridine] -5-carboxamide
  • 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) , K2CO3 (0.058g, 0.42 mmol) , and [Pd (PPh3) 2Cl2] (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 N2 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) . The combined organic layers were dried over Na2SO4 and then the solvent was removed in vacuo. The residue thus obtained was redissolved in 10 mL of a solvent mixture of AcOH/H2O in a ratio of 80/20. The solution was heated at reflux for 5 h. Then, after cooling down the reaction to room temperature, the solvent was removed in vacuo, and the residue was redisolved in saturated solution of NaHCO3 (25mL) and EtOAc (25 mL) and was added. The mixture was transferred into a separation funnel, extracted and the aqueous phase was washed with EtOAc (25 mL) . The organic layers were combined, dried over Na2SO4 and then the solvent was removed in vacuo. The residue was purified by flash chromatography (0-100％Solvent B/hexane, while solvent B is a solvent mixture of 10％MeOH in EtOAc) to afford a light yellow solid (0.014 g, 15 ％) . LC/MS (Rt ＝ 1.63 min, +ESI m/z: MH+ ＝ 442.3) .
  • Example 012:
  • N- (4- (chlorodifluoromethoxy) phenyl) -3- (1H-pyrazol-5-yl) - [2, 4'-bipyridine] -5-carboxamide
  • The title compound was synthesized by following the procedure for the synthesis of Example 011. The crude was purified by flash chromatography (0-100％Solvent B/hexane, while solvent B is a solvent mixture of 10％MeOH in EtOAc) to afford a light yellow solid (0.022 g, 24 ％) . LC/MS (Rt ＝ 1.63 min, +ESI m/z: MH+ ＝ 442.3) .
  • Example 013: N- (4- (chlorodifluoromethoxy) phenyl) -6-phenyl-5- (1H-pyrazol-5-yl) nicotinamide
  • The title compound was synthesized by following the procedure for the synthesis of Example 011. The crude was purified by flash chromatography (0-100％EtOAc/hexane) to afford a light yellow solid (0.042 g, 46 ％) . LC/MS (Rt ＝ 1.92 min, +ESI m/z: MH+ ＝ 441.3) .
  • Example 014: N- (4- (chlorodifluoromethoxy) phenyl) -5- (1H-pyrazol-5-yl) -6- (thiophen-3-yl) nicotinamide
  • The title compound was synthesized by following the procedure for the synthesis of Example 011. The crude was purified by flash chromatography (0-100％EtOAc/hexane) to afford a light yellow solid (0.054 g, 59 ％) . LC/MS (Rt ＝ 1.90 min, +ESI m/z: MH+ ＝ 447.3) .
  • Example 015:
  • N- (4- (chlorodifluoromethoxy) phenyl) -6- (1-methyl-1H-pyrazol-4-yl) -5- (1H-pyrazol-5-yl) nicotinamide
  • The title compound was synthesized by following the procedure for the synthesis of Example 011. The crude was purified by flash chromatography (0-100％Solvent B/hexane, while solvent B is a solvent mixture of 10％MeOH in EtOAc) to afford a light yellow solid (0.042 g, 46 ％) . LC/MS (Rt ＝ 1.71 min, +ESI m/z: MH+ ＝ 445.4) .
  • Example 016:
  • N- (4- (chlorodifluoromethoxy) phenyl) -6- (1-methyl-1H-pyrazol-5-yl) -5- (1H-pyrazol-5-yl) nicotinamide
  • The title compound was synthesized by following the procedure for the synthesis of Example 011. The crude was purified by flash chromatography (0-100％Solvent B/hexane, while solvent B is a solvent mixture of 10％MeOH in EtOAc) to afford a light yellow solid (0.022 g, 24 ％) . LC/MS (Rt ＝ 1.79 min, +ESI m/z: MH+ ＝ 445.2) .
  • Example 017:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (1-methyl-1H-pyrazol-4-yl) - [3, 3'-bipyridine] -5-carboxamide
  • To a reaction vial equipped with septum cap contained IN-3-01 (0.22 g, 0.54 mmol) , 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.167 g, 0.80 mmol) , K2CO3 (0.222 g, 1.61 mmol) , PdCl2 (PPh3) 2 (75 mg, 0.11 mmol) was added 5 mL of a solvent mixture of 20％of water in 1, 4-dioxane. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and dried over Na2SO4, filtered and evaporated onto 4 g of silica gel and purified by flash chromatography (0-100％EtOAc/hexanes) to afford a brownish solid. By trituration of this solid with 2 mL of DCM and filtered to obtain the title compound as a white solid (34 mg, 14％yield) . LC/MS (Rt ＝ 1.64 min, +ESI m/z: MH+ ＝ 456.1) .
  • Example 018:
  • N- (4- (chlorodifluoromethoxy) phenyl) -3- (1-methyl-1H-pyrazol-4-yl) - [2, 3'-bipyridine] -5-carboxamide
  • The title compound was synthesized by following the procedure for the synthesis of Example 017 from IN-3-04 (170 mg) . The crude was purified by flash chromatography (0-100％Solvent B/hexane, while solvent B is a solvent mixture of 10％MeOH in EtOAc) to afford a brownish solid. By trituration of this solid with 2 mL of DCM and filtered to obtain the title compound as a white solid (11 mg, 6％yield) . LC/MS (Rt ＝ 1.59 min, +ESI m/z: MH+ ＝ 456.2) .
  • Example 019:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (1-methyl-1H-imidazol-5-yl) - [3, 3'-bipyridine] -5-carboxamide
  • To a reaction vial equipped with septum cap contained IN-3-01 (0.20 g, 0.49 mmol) , 1-methyl-5- (tributylstannyl) -1H-imidazole (0.271 g, 0.80 mmol) , CuI (19 mg, 0.10 mmol) , Pd(PPh3) 4 (68 mg, 0.06 mmol) was added 12 mL of DMF. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 80 ℃ and stirred at this temperature overnight. The reaction was cooled to room temperature, water was added to quench the reaction and then filtered to remove some unsoluble material. The solid was washed with EtOAc. The filtrate was extracted with EtOAc, washed with water, brine, dried over Na2SO4, filtered, evaporated onto 4 g of silica gel and purified by flash chromatography (0-100％solvent B/hexanes, while the solvent B is a solvent mixture of 10％MeOH in EtOAc) to afford the desired as a yellow solid. By trituration of this solid with 2 mL of DCM and filtered to obtain the title compound as a white solid (123 mg, 55％yield) . LC/MS (Rt ＝ 1.57 min, +ESI m/z: MH+ ＝ 456.3) .
  • Example 020:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (1-methyl-1H-pyrazol-5-yl) - [3, 3'-bipyridine] -5-carboxamide
  • Method 1:
  • To a reaction vial equipped with septum cap contained IN-3-01 (0.20 g, 0.49 mmol) , (1-methyl-1H-pyrazol-5-yl) boronic acid (0.184 g, 1.46 mmol) , K2CO3 (0.673 g, 4.88 mmol) , PdCl2 (PPh3) 2 (137 mg, 0.2 mmol) was added 10 mL of a solvent mixture of 20％of water in 1,4-dioxane. After the addition, a vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and dried over Na2SO4, 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 10％MeOH in EtOAc) to afford a yellowish solid. By trituration of this solid with 2 mL of DCM and filtered to obtain the title compound as a white solid (109 mg, 49％yield) . LC/MS (Rt ＝ 1.68 min, +ESI m/z: MH+ ＝ 456.3) .
  • Method 2:
  • To a round bottom flask equipped with septum contained IN-3-01 (24.70 g, 60.21 mmol) , 1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (25.06 g, 120.43 mmol) , K2CO3 (461.86 g, 361.29 mmol) , PdCl2 (PPh3) 2 (6.34 mg, 9.03 mmol) was added 361 mL 1, 4-dioxane and 180 mL of water. After the addition, a vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The solvent was evaporated and the residue was diluted with EtOAc (600 mL) and water (500 mL) . The organic  layers was evaporated and dried over Na2SO4, filtered and evaporated onto 50 g of silica gel and purified by flash chromatography (0-100％Solvent B/hexanes, while Solvent B is a solvent mixture of 1％MeOH in EtOAc) to afford a brownish solid. This solid was redissolved in EtOAc and evaporated onto 50 g of silica gel and repeated the flash chromatography for two times to afford a white solid (25.1 g, 91％yield) . LC/MS (Rt ＝ 1.68 min, +ESI m/z: MH+ ＝ 456.3) .
  • Example 021: N- (4- (chlorodifluoromethoxy) phenyl) -5, 6-bis (1-methyl-1H-imidazol-5-yl) nicotinamide
  • To a reaction vial equipped with septum cap contained IN-1-02 (0.20 g, 0.49 mmol) , 1-methyl-5- (tributylstannyl) -1H-imidazole (0.54 g, 1.46 mmol) , CuI (19 mg, 0.10 mmol) , Pd (PPh3) 4 (68 mg, 0.06 mmol) was added 12 mL of DMF. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 80℃ and stirred at this temperature overnight. The reaction was cooled to room temperature, water was added to quench the reaction and then filtered to remove some unsoluble material. The solid was washed with EtOAc. The filtrate was extracted with EtOAc, washed with water, brine, dried over Na2SO4, filtered, evaporated onto 4 g of silica gel and purified by flash chromatography (0-100％Solvent B/DCM, while the Solvent B is a solvent mixture of 20％of concentrated ammonia in MeOH) to afford the desired as a yellow solid. By trituration of this solid with 2 mL of DCM and filtered to obtain the title compound as a white solid (107 mg, 48％yield) . LC/MS (Rt ＝ 1.52 min, +ESI m/z: MH+ ＝ 459.2) .
  • Example 022:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (3, 5-dimethylisoxazol-4-yl) - [3, 3'-bipyridine] -5-carboxamide
  • To a reaction vial equipped with septum cap contained IN-3-01 (0.22 g, 0.54 mmol) , (3, 5-dimethylisoxazol-4-yl) boronic acid (0.113 g, 0.80 mmol) , K2CO3 (0.222 g, 1.61 mmol) ,  PdCl2 (PPh3) 2 (75 mg, 0.11 mmol) was added 5 mL of a solvent mixture of 20％of water in 1, 4-dioxane. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and dried over Na2SO4, filtered and evaporated onto 4 g of silica gel and purified by flash chromatography (0-100％EtOAc/hexanes) to afford a white solid (181 mg, 72％yield) . LC/MS (Rt ＝ 1.56 min, +ESI m/z: MH+ ＝ 470.9) .
  • Example 023: N- (4- (chlorodifluoromethoxy) phenyl) -2- (o-tolyl) - [3, 3'-bipyridine] -5-carboxamide
  • To a reaction vial equipped with septum cap contained IN-3-01 (0.22 g, 0.54 mmol) , o-tolylboronic acid (0.109 g, 0.80 mmol) , K2CO3 (0.222 g, 1.61 mmol) , PdCl2 (PPh3) 2 (75 mg, 0.11 mmol) was added 5 mL of a solvent mixture of 20％of water in 1, 4-dioxane. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and dried over Na2SO4, filtered and evaporated onto 4 g of silica gel and purified by flash chromatography (0-100％ EtOAc/hexanes) to afford a white solid (161 mg, 64％yield) . LC/MS (Rt ＝ 1.64 min, +ESI m/z: MH+ ＝ 466.0) .
  • Example 024:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (3, 5-dimethyl-1H-pyrazol-1-yl) - [3, 3'-bipyridine] -5-carboxamide
  • Step 1: N- (4- (chlorodifluoromethoxy) phenyl) -2-hydrazinyl- [3, 3'-bipyridine] -5-carboxamide (IN-4-01)
  • To a sealed tube contained IN-3-01 (2.34 g, 5.70 mmol) in 100 mL of 2-propanol stirred at rt, 4.37 mL of hydrazine monohydrate was added dropwise. After the addition, the tube was sealed and the mixture was heated to 125℃ and stirred at this temperature overnight. The mixture was cooled down to rt and 20 mL of water was added. The precipitate thus formed was collected by filtration and washed with water, air dried to afford the title compound as a dark brown solid (1.20 g, 52％yield) . LC/MS (Rt ＝ 1.47 min, +ESI m/z: MH+ ＝ 406.2) .
  • Step 2:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (3, 5-dimethyl-1H-pyrazol-1-yl) - [3, 3'-bipyridine] -5-carboxamide (Example 024)
  • To a solution of IN-4-01 (0.20 g, 0.49 mmol) , and pentane-2, 4-dione (59 mg, 0.59 mmol) in 2-PrOH (10 mL) , was added AcOH (71 μL, 1.23 mmol) , and the mixture was stirred at 100 ℃ overnight in a reaction vial. LCMS showed the completed consumption of SM. Thus the reaction was worked up by the addition of NaHCO3/H2O (sat) and extracted with EtOAc, dried over Na2SO4, filtered, and evaporated. The residue was purified by flash chromatography (0-100％ EtOAc/hexanes) to afford the title compound (98 mg, 42％yield) . LC/MS (Rt ＝ 1.75 min, +ESI m/z: MH+ ＝ 470.2) .
  • Example 025:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (1H-pyrazol-1-yl) - [3, 3'-bipyridine] -5-carboxamide
  • To a solution of IN-4-01 (0.20 g, 0.49 mmol) , and 1, 1, 3, 3-tetramethoxypropane (97 mg, 0.59 mmol) in 2-PrOH (3.3 mL) in a reaction vial, was added con HCl (91 μL, 1.08 mmol) and the mixture was stirred at 80 ℃ for 2 h. LCMS showed the completed consumption of SM. Thus the reaction was worked up by the addition of NaHCO3/H2O (sat) and extracted with EtOAc, dried over Na2SO4, filtered, and evaporated. The residue was purified by flash chromatography (0-100％EtOAc/hexanes) to afford the title compound (94 mg, 43％yield) . LC/MS (Rt ＝ 1.68 min, +ESI m/z: MH+ ＝ 442.1) .
  • Example 026:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (5-methyl-1H-pyrazol-1-yl) - [3, 3'-bipyridine] -5-carboxamide
  • To a reaction vial equipped with septum cap contained IN-2-13 (0.40 g, 0.87 mmol) , pyridin-3-ylboronic acid (0.215 g, 1.75 mmol) , K2CO3 (0.724 g, 5.24 mmol) , PdCl2 (PPh3) 2 (123 mg, 0.17 mmol) was added 17 mL of a solvent mixture of 20％of water in 1, 4-dioxane. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and dried over Na2SO4, 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 1％MeOH in EtOAc) to afford the title compound as a white solid (14 mg, 4％yield) . LC/MS (Rt ＝ 1.73 min, +ESI m/z: MH+ ＝ 456.2) .
  • Example 027:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (3-methyl-1H-pyrazol-1-yl) - [3, 3'-bipyridine] -5-carboxamide
  • To a reaction vial equipped with septum cap contained IN-2-12 (0.40 g, 0.87 mmol) , pyridin-3-ylboronic acid (0.215 g, 1.75 mmol) , K2CO3 (0.724 g, 5.24 mmol) , PdCl2 (PPh3) 2 (123 mg, 0.17 mmol) was added 17 mL of a solvent mixture of 20％of water in 1, 4-dioxane. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and dried over Na2SO4, 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 1％MeOH in EtOAc) to afford the title compound as a white solid (390 mg, 98％yield) . LC/MS (Rt ＝ 1.73 min, +ESI m/z: MH+ ＝ 455.0) .
  • Example 028:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (1-methyl-1H-pyrazol-5-yl) - [3, 3'-bipyridine] -5-carboxamide
  • To a reaction vial equipped with septum cap contained IN-3-05 (0.20 g, 0.44 mmol) , 1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.203 g, 0.98 mmol) , K2CO3 (0.405 g, 2.93 mmol) , PdCl2 (PPh3) 2 (51 mg, 0.07 mmol) was added 5 mL of a solvent mixture of 20％of water in 1, 4-dioxane. After the addition, a vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and dried over Na2SO4, 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 1％MeOH in EtOAc) to afford the title compound as a white solid (160 mg, 72％yield) . LC/MS (Rt ＝ 1.58 min, +ESI m/z: MH+ ＝ 455.0) .
  • Example 029:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2'-methyl-2- (pyridin-3-yl) - [1, 1'-biphenyl] -4-carboxamide
  • Method 1:
  • The title compound was preped from IN-3-05 (0.20 g, 0.44 mmol) , o-tolylboronic acid (0.133 g, 0.98 mmol) , K2CO3 (0.405 g, 2.93 mmol) , PdCl2 (PPh3) 2 (51 mg, 0.07 mmol) by following the procedure for Example 028 as a white solid (200 mg, 98％yield) . LC/MS (Rt ＝ 1.81 min, +ESI m/z: MH+ ＝ 465.0) .
  • Example 030:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (2- (trifluoromethyl) phenyl) - [3, 3'-bipyridine] -5-carboxamide
  • To a reaction vial equipped with septum cap contained IN-3-01 (0.20 g, 0.49 mmol) , (2- (trifluoromethyl) phenyl) boronic acid (0.185 g, 0.98 mmol) , K2CO3 (0.404 g, 2.93 mmol) , PdCl2 (PPh3) 2 (51 mg, 0.07 mmol) was added 5 mL of a solvent mixture of 20％of water in 1, 4-dioxane. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and dried over Na2SO4, 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 1％MeOH in EtOAc) to afford a white solid (239 mg, 94％yield) . LC/MS (Rt ＝ 1.70 min, +ESI m/z: MH+ ＝ 520.0) .
  • Example 031: N- (4- (chlorodifluoromethoxy) phenyl) -2- (2-ethylphenyl) - [3, 3'-bipyridine] -5-carboxamide
  • The title compound was prepared from IN-3-01 (0.20 g, 0.49 mmol) , (2-ethylphenyl) boronic acid (0.146 g, 0.98 mmol) , K2CO3 (0.404 g, 2.93 mmol) , PdCl2 (PPh3) 2 (51 mg, 0.07 mmol) by following the procedure for Example 030 as a white solid (228 mg, 97％yield) . LC/MS (Rt ＝ 1.71 min, +ESI m/z: MH+ ＝ 480.0) .
  • Example 032:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (2-methoxyphenyl) - [3, 3'-bipyridine] -5-carboxamide
  • The title compound was prepared from IN-3-01 (0.20 g, 0.49 mmol) , (2-methoxyphenyl) boronic acid (0.148 g, 0.98 mmol) , K2CO3 (0.404 g, 2.93 mmol) , PdCl2 (PPh3) 2 (51 mg, 0.07 mmol) by following the procedure for Example 030 as a white solid (234 mg, 100％yield) . LC/MS (Rt ＝ 1.60 min, +ESI m/z: MH+ ＝ 482.1) .
  • Example 033: N- (4- (chlorodifluoromethoxy) phenyl) -2- (2-fluorophenyl) - [3, 3'-bipyridine] -5-carboxamide
  • The title compound was prepared from IN-3-01 (0.20 g, 0.49 mmol) , (2-fluorophenyl) boronic acid (0.136 g, 0.98 mmol) , K2CO3 (0.404 g, 2.93 mmol) , PdCl2 (PPh3) 2 (51 mg, 0.07 mmol) by  following the procedure for Example 030 as a white solid. (229 mg, 100％yield) . LC/MS (Rt ＝1.64 min, +ESI m/z: MH+ ＝ 470.0) .
  • Example 034:
  • 2- (2-carbamoylphenyl) -N- (4- (chlorodifluoromethoxy) phenyl) - [3, 3'-bipyridine] -5-carboxamide
  • The title compound was prepared from IN-3-01 (0.20 g, 0.49 mmol) , (2-cyanophenyl) boronic acid (0.136 g, 0.98 mmol) , K2CO3 (0.404 g, 2.93 mmol) , PdCl2 (PPh3) 2 (51 mg, 0.07 mmol) by following the procedure for Example 030. The compound 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 white solid. (169 mg, 70％yield) . LC/MS (Rt ＝ 1.42 min, +ESI m/z: MH+ ＝ 495.0) .
  • Example 035: N- (4- (chlorodifluoromethoxy) phenyl) -5- (pyrimidin-5-yl) -6- (o-tolyl) nicotinamide
  • The title compound was prepared from IN-3-02 (0.20 g, 0.49 mmol) , o-tolylboronic acid (0.132 g, 0.97 mmol) , K2CO3 (0.403 g, 2.92 mmol) , PdCl2 (PPh3) 2 (51 mg, 0.07 mmol) by following the procedure for Example 030 as a white solid. (141 mg, 62％yield) . LC/MS (Rt ＝ 1.90 min, +ESI m/z: MH+ ＝ 467.0) .
  • Example 036:
  • N- (4- (chlorodifluoromethoxy) phenyl) -6- (1-methyl-1H-pyrazol-5-yl) -5- (pyrimidin-5-yl) nicotinamide
  • The title compound was prepared from IN-3-02 (0.20 g, 0.49 mmol) , (1-methyl-1H-pyrazol-5-yl) boronic acid (0.123 g, 0.97 mmol) , K2CO3 (0.403 g, 2.92 mmol) , PdCl2 (PPh3) 2 (51 mg, 0.07 mmol) by following the procedure for Example 030 as a white solid. (156 mg, 69％yield) . LC/MS (Rt ＝ 1.72 min, +ESI m/z: MH+ ＝ 457.1) .
  • Example 037: N- (4- (chlorodifluoromethoxy) phenyl) -5, 6-di (1H-pyrazol-4-yl) nicotinamide
  • The title compound was synthesized by following the procedure described above for the synthesis of Example 006 from 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole to afford the title compound (0.064 g, 70％yield) . LC/MS (Rt ＝ 1.75 min, +ESI m/z: MH+ ＝ 459.3) .
  • Example 038: 5, 6-di (1H-pyrazol-5-yl) -N- (4- (trifluoromethoxy) phenyl) nicotinamide
  • To a round bottom flask containing IN-1-01 (1.0 g, 2.53 mmol) , 1- (tetrahydro-2H-pyran-2-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (2.11 g, 7.58 mmol) , K3PO4 (3.22 g, 15.17 mmol) , and [Pd (PPh3) 4] (292 mg, 0.25 mmol) under vacuum, toluene (30  mL) was added via syringe. A nitrogen balloon was applied and the mixture was heated at 110 ℃ overnight. The mixture was cooled down to rt and added to a separation funnel with water. The flask was washed with EtOAc and added to the separation funnel. The organic phase was separated, dried over Na2SO4, filtered and evaporated. The crude thus obtained was redissolved in 20 mL of DCM and was treated with 6 mL of TFA at rt overnight. The LCMS showed that reaction was not finished. Thus the reaction was worked up by evaporation of the solvent and the residue was redissolved in 10 mL of 80％AcOH in water and heated to 100℃ overnight. The solvent was evaporated and the residue was purified by flash chromatography (0-5％MeOH/DCM) . The compound was still not pure thus was swished with DCM and filtered to collect the title compound as a white solid (351 mg, 36％yield) . LC/MS (Rt ＝ 1.70 min, +ESI m/z: MH+ ＝ 415.2) .
  • Example 039:
  • N- (4- (chlorodifluoromethoxy) phenyl) -6'-fluoro-2- (1-methyl-1H-pyrazol-5-yl) - [3, 3'-bipyridine] -5-carboxa mide
  • The title compound was prepared from IN-3-06 (1, 54 g, 3.60 mmol) , (1-methyl-1H-pyrazol-5-yl) boronic acid (0.91 g, 7.19 mmol) , K2CO3 (2.98 g, 21.58 mmol) , PdCl2 (PPh3) 2 (378 mg, 0.54 mmol) by following the procedure for Example 030 as a white solid. (1.10 g, 65％yield) . LC/MS (Rt ＝ 1.89 min, +ESI m/z: MH+ ＝ 473.9) .
  • Example 040: N- (4- (chlorodifluoromethoxy) phenyl) -5- (1H-pyrazol-5-yl) -6- (o-tolyl) nicotinamide
  • The title compound was prepared from IN-3-07 (0.20 g, 0.50 mmol) , o-tolylboronic acid (0.136 g, 1.00 mmol) , K2CO3 (0.416 g, 3.01 mmol) , PdCl2 (PPh3) 2 (53 mg, 0.08 mmol) by following  the procedure for Example 030 as a white solid. (13 mg, 6％yield) . LC/MS (Rt ＝ 1.81 min, +ESI m/z: MH+ ＝ 455.0) .
  • Example 041:
  • N- (4- (chlorodifluoromethoxy) phenyl) -6'- ( (4-methoxybenzyl) amino) -2- (1-methyl-1H-pyrazol-5-yl) - [3, 3'-bipyridine] -5-carboxamide
  • A mixture of Example 039 (0.22 g, 0.46 mmol) , (4-methoxyphenyl) methanamine (0.446 g, 3.25 mmol) , in 15 mL of 1, 4-dioxane was heated to 100℃ and stirred at this temperature overnight. LCMS showed that 15％of reaction was observed. Thus another 1.0 g of (4-methoxyphenyl) methanamine was added and heated for 2 days. The solvent was evaporated and the residue was purified by flash chromatography (0-100％solvent B/hexane, while solvent B is a solvent mixture of 5％MeOH in EtOAc) to afford the title compound as a yellowish solid. (274 mg, 100％yield) . LC/MS (Rt ＝ 1.70 min, +ESI m/z: MH+ ＝ 591.0) .
  • Example 042:
  • N- (4- (chlorodifluoromethoxy) phenyl) -6'-hydrazinyl-2- (1-methyl-1H-pyrazol-5-yl) - [3, 3'-bipyridine] -5-car boxamide
  • A mixture of 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) . LC/MS (Rt ＝ 1.51 min, +ESI m/z: MH+ ＝ 486.0) .
  • Example 043:
  • 5- ( [1, 2, 4] triazolo [4, 3-a] pyridin-6-yl) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (1-methyl-1H-pyrazol-5-yl ) nicotinamide
  • A mixture of Example 042 (0.226 g, 0.46 mmol) and trimethyl orthoformate (10.32 g, 69.95 mmol) was heated to 100℃ and stirred at this temperature overnight. The solvent was evaporated to dryness under high vacuum and the residue was purified by flash chromatography (0-100％solvent B/hexanes, while solvent B is a solvent mixture of 5％MeOH in EtOAc) to afford the desired. Then purified by flash chromatography with 43 g of C18 column (5-100％MeCN/water) to afford the desired as a white solid. (92 mg, 40％yield) . LC/MS (Rt ＝ 1.56 min, +ESI m/z: MH+ ＝ 495.9) .
  • Example 044:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (1-methyl-1H-pyrazol-5-yl) -6'- (methylamino) - [3, 3'-bipyridine] -5 -carboxamide
  • A mixture of Example 039 (0.22 g, 0.46 mmol) , 40％methanamine (0.819 g, 10.55 mmol) in 15 mL of 1, 4-dioxane was heated to 90℃ and stirred at this temperature for 3 days in a sealed tube. The solvent was evaporated to dryness under high vacuum and the residue was purified by FLC (0-100％solvent B/hexanes, while solvent B is a solvent mixture of 10％MeOH in EtOAc) to afford the title compound as a yellowish solid. (99 mg, 97％yield) . LC/MS (Rt ＝ 1.55 min, +ESI m/z: MH+ ＝ 485.0) .
  • Example 045:
  • N- (4- (chlorodifluoromethoxy) phenyl) -6'- (dimethylamino) -2- (1-methyl-1H-pyrazol-5-yl) - [3, 3'-bipyridine] -5-carboxamide
  • A mixture of Example 039 (0.22 g, 0.46 mmol) , 40％dimethylamine (1.189 g, 10.55 mmol) in 15 mL of 1, 4-dioxane was heated to 90℃ and stirred at this temperature for 3 days in a sealed tube. The solvent was evaporated to dryness under high vacuum and the residue was purified by FLC (0-100％solvent B/hexanes, while solvent B is a solvent mixture of 5％MeOH in EtOAc) to afford the title compound as a yellowish solid. (94 mg, 89％yield) . LC/MS (Rt ＝ 1.57 min, +ESI m/z: MH+ ＝ 499.0) .
  • Example 046:
  • N- (4- (chlorodifluoromethoxy) phenyl) -6'- ( (2-hydroxyethyl) amino) -2- (1-methyl-1H-pyrazol-5-yl) - [3, 3'-bip yridine] -5-carboxamide
  • A mixture of Example 039 (0.22 g, 0.46 mmol) , 2-aminoethanol (0.647 g, 10.55 mmol) in 15 mL of 1, 4-dioxane was heated to 100℃ and stirred at this temperature for 3 days in a sealed tube. The solvent was evaporated to dryness under high vacuum and the residue was purified by FLC (0-100％solvent B/hexanes, while solvent B is a solvent mixture of 10％MeOH in EtOAc) to afford the title compound as a yellowish solid. (73 mg, 67％yield) . LC/MS (Rt ＝ 1.49 min, +ESI m/z: MH+ ＝ 515.2) .
  • Example 047:
  • 6'-amino-N- (4- (chlorodifluoromethoxy) phenyl) -2- (1-methyl-1H-pyrazol-5-yl) - [3, 3'-bipyridine] -5-carboxa mide
  • A mixture of Example 041 (274 mg, 0.46 mmol) , diphenyl ether (786 mg. 4.62 mmol) in TFA (15 mL) was to 75℃ and stirred at this temperature for 3 hr. The solvent was evaporated and the residue was redissolved in EtOAc and washed with sat NaHCO3/H2O solution. The organic layer was dried over Na2SO4 and filtered. The solvent was evaporated and the residue was purified by flash chromatography (0-100％solvent B/hexanes, while solvent B is a solvent mixture of 10％MeOH in EtOAc) to afford the title compound as a light yellowish solid. (131 mg, 60％yield) . LC/MS (Rt ＝ 1.51 min, +ESI m/z: MH+ ＝ 471.1) .
  • Example 048: N- (4- (chlorodifluoromethoxy) phenyl) -2-phenyl- [3, 3'-bipyridine] -5-carboxamide
  • To a reaction vial equipped with septum cap contained IN-3-01 (0.15 g, 0.37 mmol) , phenylboronic acid (0.089 g, 0.73 mmol) , K2CO3 (0.303 g, 2.19 mmol) , Pd (DPPF) Cl2 (40 mg, 0.05 mmol) was added 3.7 mL of a solvent mixture of 20％of water in 1, 4-dioxane. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and dried over Na2SO4, 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 1％ MeOH in EtOAc) to afford a solid tinted with brownish color. The solid was further purified by flash chromatography with 43 g of C18 column (5-100％MeCN/water) to afford the desired as a white solid. (106 mg, 64％yield) . LC/MS (Rt ＝ 1.62 min, +ESI m/z: MH+ ＝ 452.0) .
  • Example 049: N- (4- (chlorodifluoromethoxy) phenyl) -2- (thiophen-3-yl) - [3, 3'-bipyridine] -5-carboxamide
  • The title compound was prepared by following the procedure described for Example 48, from IN-3-01 (0.15 g, 0.37 mmol) , thiophen-3-ylboronic acid (0.084 g, 0.73 mmol) , K2CO3 (0.303 g, 2.19 mmol) , Pd (DPPF) Cl2 (40 mg, 0.05 mmol) . Flash chromatography (0-100％solent B/hexanes, while  solvent B is a solvent mixture of 1％MeOH in EtOAc) and flash chromatography with 43 g of C18 column (5-100％MeCN/water) to afford the desired as a white solid. (104 mg, 62％yield) . LC/MS (Rt ＝ 1.61 min, +ESI m/z: MH+ ＝ 458.0) .
  • Example 050:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) - [3, 3'-bipyridine] -5-carbox amide
  • The title compound was prepared by following the procedure described for Example 48, from IN-3-01 (0.15 g, 0.37 mmol) , (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) boronic acid (0.114 g, 0.73 mmol) , K2CO3 (0.303 g, 2.19 mmol) , Pd (DPPF) Cl2 (40 mg, 0.05 mmol) . Flash chromatography (0-100％solent B/hexanes, while solvent B is a solvent mixture of 10％MeOH in EtOAc) and flash chromatography with 43 g of C18 column (5-100％MeCN/water) to afford the desired as a white solid. (57 mg, 32％yield) . LC/MS (Rt ＝ 1.45 min, +ESI m/z: MH+ ＝ 486.1) .
  • Example 051:
  • N- (4- (chlorodifluoromethoxy) phenyl) -6- (1-methyl-1H-pyrazol-4-yl) -5- (pyrimidin-5-yl) nicotinamide
  • The title compound was prepared by following the procedure described for Example 48, from IN-3-02 (0.15 g, 0.36 mmol) , 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.152 g, 0.73 mmol) , K2CO3 (0.303 g, 2.19 mmol) , Pd (DPPF) Cl2 (40 mg, 0.05 mmol) . Flash chromatography (0-100％solent B/hexanes, while solvent B is a solvent mixture of 10％MeOH in EtOAc) and flash chromatography with 43 g of C18 column (5-100％MeCN/water) to afford the desired as a white solid. (57 mg, 32％yield) . LC/MS (Rt ＝ 1.69 min, +ESI m/z: MH+ ＝ 457.1) .
  • Example 052:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2'-fluoro-2- (1-methyl-1H-pyrazol-4-yl) - [3, 3'-bipyridine] -5-carboxa mide
  • 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) , K2CO3 (0.464 g, 3.36 mmol) , Pd (DPPF) Cl2 (62 mg, 0.08 mmol) . Flash chromatography (0-100％solent B/hexanes, while solvent B is a solvent mixture of 10％MeOH in EtOAc) and flash chromatography with 43 g of C18 column (5-100％MeCN/water) to afford the desired as a white solid. (94 mg, 35％yield) . LC/MS (Rt ＝ 1.84 min, +ESI m/z: MH+ ＝ 474.1) .
  • Example 053:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2'-fluoro-2- (1-methyl-1H-pyrazol-5-yl) - [3, 3'-bipyridine] -5-carboxa mide
  • 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) , K2CO3 (0.464 g, 3.36 mmol) , Pd (DPPF) Cl2 (62 mg, 0.08 mmol) . Flash chromatography (0-100％solent B/hexanes, while solvent B is a solvent mixture of 10％MeOH in EtOAc) and flash chromatography with 43 g of C18 column (5-100％MeCN/water) to afford the desired as a white solid. (117 mg, 44％yield) . LC/MS (Rt ＝ 1.85 min, +ESI m/z: MH+ ＝ 473.9) .
  • Example 054: N- (4- (chlorodifluoromethoxy) phenyl) -2- (2-chlorophenyl) - [3, 3'-bipyridine] -5-carboxamide
  • The title compound was prepared from IN-3-01 (0.20 g, 0.49 mmol) , (2-chlorophenyl) boronic acid (0.153 g, 0.98 mmol) , K2CO3 (0.404 g, 2.93 mmol) , PdCl2 (PPh3) 2 (51 mg, 0.07 mmol) by following the procedure for Example 030. Flash chromatography (0-100％solent B/hexanes, while solvent B is a solvent mixture of 1％MeOH in EtOAc) and then purified by HPLC with C18 column (35-95％MeCN/water) to afford the desired as a white solid. (109 mg, 46％yield) . LC/MS (Rt ＝ 1.64 min, +ESI m/z: MH+ ＝ 485.8/487.8) .
  • Example 055:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (1H-pyrazol-4-yl) - [3, 3'-bipyridine] -5-carboxamide
  • The title compound was prepared by following the procedure described for Example 48, from IN-3-01 (0.15 g, 0.36 mmol) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.142 g, 0.73 mmol) , K2CO3 (0.303 g, 2.19 mmol) , Pd (DPPF) Cl2 (40 mg, 0.05 mmol) . Flash chromatography (0-100％solent B/hexanes, while solvent B is a solvent mixture of 10％MeOH in EtOAc) and HPLC with C18 column (30-95％MeCN/water) to afford the desired as a white solid. (62 mg, 38％yield) . LC/MS (Rt ＝ 1.47 min, +ESI m/z: MH+ ＝ 441.9) .
  • Example 056:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) - [3, 3'-bipyridine] -5-carboxamide
  • 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) , K2CO3 (0.303 g, 2.19 mmol) , Pd (DPPF) Cl2 (40 mg, 0.05 mmol) . Flash chromatography (0-100％solent B/hexanes, while solvent B is a solvent mixture of 10％MeOH in EtOAc) and HPLC with C18 column (30-95％MeCN/water) to afford the desired as a white solid. (190 mg, 99％yield) . LC/MS (Rt ＝ 1.65 min, +ESI m/z: MH+ ＝ 526.0) .
  • Example 057:
  • N- (4- (chlorodifluoromethoxy) phenyl) -6- (1-methyl-1H-imidazol-5-yl) -5- (pyrimidin-5-yl) nicotinamide
  • To a reaction vial equipped with septum cap contained IN-3-01 (0.15 g, 0.36 mmol) , 1-methyl-5- (tributylstannyl) -1H-imidazole (0.203 g, 0.55 mmol) , CuI (14 mg, 0.07 mmol) , Pd(PPh3) 4 (51 mg, 0.04 mmol) was added 9 mL of DMF. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 80 ℃ and stirred at this temperature overnight. The reaction was cooled to room temperature, water was added to quench the reaction and then filtered to remove some unsoluble material. The solid was washed with EtOAc. The filtrate was extracted with EtOAc, washed with water, brine, dried over Na2SO4, filtered, evaporated onto 4 g of silica gel and purified by flash chromatography (0-100％solvent B/hexanes, while the solvent B is a solvent mixture of 10％MeOH in EtOAc) to afford the desired as a yellow solid which was further purified by HPLC with C18 column (30-95％MeCN/water) to afford the desired as a white solid. (34 mg, 20％yield) . LC/MS (Rt ＝ 1.48 min, +ESI m/z: MH+ ＝ 456.9) .
  • Example 058:
  • N- (4- (chlorodifluoromethoxy) phenyl) -2- (1H-pyrazol-5-yl) - [3, 3'-bipyridine] -5-carboxamide
  • To a solution of Example 56 (0.186 g, 0.35 mmol) in 10 mL of MeOH stirred at rt in a reaction vial, was added 2 mL of 2 M H3PO4. The mixture was stirred at 65℃ for 3 hr. The solvent was evaporated and the residue was treated with water and neutralized with sat NaHCO3/H2O and extracted with EtOAc, dried over Na2SO4, evaporated. The residue was purified by HPLC with C18 column (30-95％MeCN/water) to afford the title compound as a white solid. (41 mg, 26％yield) . LC/MS (Rt ＝ 1.46 min, +ESI m/z: MH+ ＝ 441.9) .
  • Example 059: methyl 4- (5- ( (4- (chlorodifluoromethoxy) phenyl) carbamoyl) - [3, 3'-bipyridin] -2-yl) benzoate
  • To a reaction vial equipped with septum cap contained IN-3-01 (0.20 g, 0.49 mmol) , (4- (methoxycarbonyl) phenyl) boronic acid (0.176 g, 0.98 mmol) , K3PO4 (0.621 g, 2.93 mmol) , Pd(DPPF) Cl2 (54 mg, 0.07 mmol) was added 5 mL of a solvent mixture of 20％of water in 1, 4-dioxane. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and dried over Na2SO4, 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 1％MeOH in EtOAc) to afford the title compound as a yellowish solid. (190 mg, 76％yield) . LC/MS (Rt ＝ 1.59 min, +ESI m/z: MH+ ＝ 509.9) .
  • Example 060: methyl 4- (5- ( (4- (chlorodifluoromethoxy) phenyl) carbamoyl) - [3, 3'-bipyridin] -2-yl) benzoate
  • To a reaction vial equipped with septum cap contained IN-3-01 (0.20 g, 0.49 mmol) , (3- (methoxycarbonyl) phenyl) boronic acid (0.176 g, 0.98 mmol) , K3PO4 (0.621 g, 2.93 mmol) , Pd(DPPF) Cl2 (54 mg, 0.07 mmol) was added 5 mL of a solvent mixture of 20％of water in 1, 4-dioxane. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. The mixture was diluted with EtOAc and dried over Na2SO4, 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 1％MeOH in EtOAc) to afford the title compound as a yellowish solid. (218 mg, 88％yield) . LC/MS (Rt ＝ 1.68 min, +ESI m/z: MH+ ＝ 509.9) .
  • Example 061: 4- (5- ( (4- (chlorodifluoromethoxy) phenyl) carbamoyl) - [3, 3'-bipyridin] -2-yl) benzoic acid
  • To a solution of Example 059 (100 mg) in 1, 4-dioxane (10 mL) in a reaction tube was added 1 mL of 1 M NaOH and the tube was sealed and heated at 70 ℃ for 30 min. LCMS showed that reaction done. The reaction was worked up by evaporation and the residue was redissolved in water and treated with 0.20 mL of AcOH. The precipitate thus formed was collected by filtration, washed with water, TBME, and then air dried to afford 66 mg of the title compound as an off-white solid. LC/MS (Rt ＝ 1.52 min, +ESI m/z: MH+ ＝ 495.9) .
  • Example 062: N- (4- (chlorodifluoromethoxy) phenyl) -2- (2-cyanophenyl) - [3, 3'-bipyridine] -5-carboxamide
  • To a solution of Example 034 (153 mg, 0.31 mmol) and Et3N (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 NaHCO3/H2O, extracted with DCM and dried over Na2SO4, 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. The solid was further purified by flash chromatography over 43 g of C18 column (30-95％MeCN/H2O) to afford the the title compound as an off-white solid. (61 mg,41％yield) . LC/MS (Rt ＝ 1.77 min, +ESI m/z: MH+ ＝ 477.1) .
  • Example 063: 3- (5- ( (4- (chlorodifluoromethoxy) phenyl) carbamoyl) - [3, 3'-bipyridin] -2-yl) benzoic acid
  • To a reaction vial equipped with septum cap contained IN-3-01 (0.15 g, 0.37 mmol) , 3-boronobenzoic acid (0.121 g, 0.73 mmol) , K2CO3 (0.303 g, 2.19 mmol) , Pd (DPPF) Cl2 (40 mg, 0.05 mmol) was added 4 mL of a solvent mixture of 20％of water in 1, 4-dioxane. After the addition, vacuum was applied right away until the bubbling get less and then a nitrogen atmosphere was established with a nitrogen balloon. The mixture was heated to 100℃ and stirred at this temperature overnight. 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 Na2SO4, 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 C18 flash with a 43 g C18 column (30-95％MeCN/water) and the impurity still existed. Re-purified by flash chromatography (0-100％solent B/hexanes, while solvent B is a solvent mixture of 15％MeOH in EtOAc) again to afford the title compound as a white solid. (13 mg, 7％yield) . LC/MS (Rt ＝ 1.55 min, +ESI m/z: MH+ ＝ 495.9) .
  • Example 064: N- (4- (chlorodifluoromethoxy) phenyl) -2- (3-cyanophenyl) - [3, 3'-bipyridine] -5-carboxamide
  • The title compound was prepared by following the procedure described for Example 48, from IN-3-01 (0.15 g, 0.36 mmol) , (3-cyanophenyl) boronic acid (0.108 g, 0.73 mmol) , K2CO3 (0.303 g, 2.19 mmol) , Pd (DPPF) Cl2 (40 mg, 0.05 mmol) . Flash chromatography (0-100％solent B/hexanes, while solvent B is a solvent mixture of 2％MeOH in EtOAc) to afford the title compound as a yellowish solid. (163 mg, 93％yield) . LC/MS (Rt ＝ 1.65 min, +ESI m/z: MH+ ＝ 476.9) .
  • Example 065: N- (4- (chlorodifluoromethoxy) phenyl) -2- (3-cyanophenyl) - [3, 3'-bipyridine] -5-carboxamide
  • The title compound was prepared by following the procedure described for Example 48, from IN-3-01 (0.15 g, 0.36 mmol) , (4-cyanophenyl) boronic acid (0.108 g, 0.73 mmol) , K2CO3 (0.303 g, 2.19 mmol) , Pd (DPPF) Cl2 (40 mg, 0.05 mmol) . Flash chromatography (0-100％solent B/hexanes, while solvent B is a solvent mixture of 2％MeOH in EtOAc) to afford the title compound as a yellowish solid. (146 mg, 84％yield) . LC/MS (Rt ＝ 1.64 min, +ESI m/z: MH+ ＝ 476.9) .
  • Example 066:
  • 2- (3-carbamoylphenyl) -N- (4- (chlorodifluoromethoxy) phenyl) - [3, 3'-bipyridine] -5-carboxamide
  • To a solution of Example 064 (130 mg, 0.27 mmol) in DMSO (5 mL) , was added K2CO3 and the mixture was stirred at rt for 5 min. To the mixture thus obtained stirred at rt was added 30％of H2O2 (185 μL, 1.64 mmol) and the mixture was stirred at rt for 5 hr. The reaction was worked up by the addition of water and the mixture was filtered to collect the precipitate formed, washed with water, air-dried to afford the title compound as an off-white solid. (100 mg, 74％yield) . LC/MS (Rt ＝ 1.44 min, +ESI m/z: MH+ ＝ 494.9) .
  • Example 067:
  • 2- (4-carbamoylphenyl) -N- (4- (chlorodifluoromethoxy) phenyl) - [3, 3'-bipyridine] -5-carboxamide
  • To a solution of Example 065 (130 mg, 0.27 mmol) in DMSO (5 mL) , was added K2CO3 and the mixture was stirred at rt for 5 min. To the mixture thus obtained stirred at rt was added 30％of H2O2 (185 μL, 1.64 mmol) and the mixture was stirred at rt for 5 hr. The reaction was worked up by the addition of water and the mixture was filtered to collect the precipitate formed, washed with water, air-dried to afford the title compound as an off-white solid. (94 mg, 70％yield) . LC/MS (Rt ＝ 1.45 min, +ESI m/z: MH+ ＝ 494.9) .
  • Biological Examples
  • Effect of the compound of the present invention on the viability of the cells expressing native (K562) or T315I BCR-ABL (BaF3/BCR-ABLT315I)
  • 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 byIII 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 pSRα. Site mutation T315I was introduced into full length BCR-ABL by overlapping PCR with the primers containing the mutation site. 293T cells (ATCC) were transiently transfected with pSRα 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. GI50 (50％growth inhibition) values are reported as the mean of three independent experiments.
  • Results: The above assays were used to evaluate the synthetic examples and the results are listed in following Table. ABL001 was used as reference compound in the assays.
  • Table R‐1: GI50 (nM) on K562 and BaF3/BCR-ABLT315I
  • Oral efficacy study of the compound the present invention in a subcutaneous K562 tumor model dependent on native BCR-ABL in mice
  • This study examined the effect of oral administration with the compound of Example 20 (AST135) to SCID mice harboring subcutaneous tumor xenografts of the K562 human CML cell line expressing native BCR-ABL. Mice were treated with AST135 twice a day for 14 days. For comparison, the commercial drug ABL001 was included in this study.
  • Tumor volume and animal body weight were measured at least twice per week. When the average tumor volume reached approximately 200 mm3, animals were randomized for grouping for treatment. Each group has 4 mice. Tumor volume was measured in two dimensions using a caliper three times a week (volume＝ L x W2 x 0.5) .
  • Results: At the dose of 30 mg/kg twice daily, AST135 (with TGI 107％) is much more efficient than the commercial compound ABL001 (with TGI 87％) in inhibiting growth of K562 xenograft growth.
  • TGI ＝ 1- [ (Vtend -Vtstarting) / (Vvend -Vvstarting) ] , wherein Vtend is the tumor volume at the end of treatment group, Vtstarting is the tumor volume at the starting of treatment group, Vvend is the tumor volume at the end of vehicle group, Vvstarting is the tumor volume at the starting of vehicle group.

Claims (18)

  1. A compound of formula (I) :
    or a pharmaceutically acceptable salt thereof, wherein:
    Each -R1 is selected from -SF5, -CF3, -CF2Cl, -CF2Br, -CF2CF3, -CF2CF2Cl, -CF (CF3) 2, -CF2H, -CF2CF2H, -CH (CF3) 2；
    Each -L- is selected from a bond, -CF2-, -O-, -S (＝O) m-, -NRLN-； wherin each -RLN is selected from -H, -CH3, -CF3, -CF2H；
    Each -R2 is selected from -H, -F, -Cl, -Br；
    Each -Q＝ is selected from -CH＝, -N＝；
    Each -Z＝ is selected from -CRZ＝, -N＝； wherein Each -RZ is selected from -H, -F, -Cl, -Br, -ORO, -NRN1RN2；
    Each R3 is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl；
    Each -R4 is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl； or
    each -R4 is selected from a moiety listed as follows:
    wherein the carbon-hydrogen bonds in the above listed moieties can be replaced with one to three carbon-R groups, wherein each -R is selected from -F, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl；
    Each RO is selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl；
    Each RN1 and RN2 are independently selected from hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, or substituted or unsubstituted 6-10 membered aryl；
    Each RP is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl；
    Wherein one or two carbon of the said substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-8 cycloalkyl may be replaced by -O-, -N (RN0) -, -S (＝O) m-, -P (RP) (＝O) -；
    Each RN0 is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl；
    m is 0, 1, or 2.
  2. The compound according to claim 1, wherein said compound is represented as the compound of formula (II) ,
    or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, L, and Z is as defined in claim 1.
  3. The compound according to claim 2, wherein said compound is represented as the compound of formula (III) ,
    or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R4, L, and Z is as defined in claim 1.
  4. The compound according to claim 3, wherein said compound is represented as the compound of formula (IIIa) ,
    or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R4, and L is as defined in claim 1.
  5. The compound according to claim 3, wherein said compound is represented as the compound of formula (IIIb) ,
    or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R4, RZ and L is as defined in claim 1.
  6. The compound according to any one of claims 1-5, wherein L is O.
  7. The compound according to claim 4, wherein:
    -R1 is -CF3, -CF2Cl, or -CF2Br；
    -L- is -O- or -S (＝O) m-；
    Each of R3 and R4 is independently selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 6-10 membered aryl.
  8. A method for preparation of the compound according to claim 1, including:
    wherein IN-3 can react with an amine derivative under conditions such as heating in the presence of absence of a base, with or without a transition metal complex as a catalyst, to covert the C-X4 bond to C-R4； or 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-X4 bond and formed the C-R4 bond when catalyzed by a transition metal such as palladium, nickle complex；
    wherein X4 is I, Br, or Cl.
  9. A method for preparation of the compound according to claim 1, including:
    wherein IN-2 can react with substituted or unsubstituted 5-10 membered heteroaryl metallic reagent, boron derivative, silicon derivative at the C-X3 bond with transition metal complex as a catalyst and formed the C-R3 bond；
    wherein X3 is I, Br, or Cl.
  10. The method according to claim 8, wherein said amine derivative is selected from:
  11. A composition comprising the compound according to any one of claims 1-7 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  12. The composition according to claim 11, further comprise an additional therapeutic agent.
  13. The composition according to claim 12, wherein the additional therapeutic agent is a chemotherapeutic agent.
  14. A method for inhibiting at least tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1 selectively in comparison to inhibition of kinase selected from ErbBl, ErbB2, ErbB4, TEC, BTK, ITK, BMX, JAK3, or RLK in a biological sample or in a patient, comprising contacting the biological sample with, or administering to the patient, a compound according to any of claims 1 to 7, or a composition according to any one claims 11-13.
  15. The method according to claim 14, wherein the at least one kniase is tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1.
  16. A method for treating a tyrosine kinase Abelson protein (ABL1) , Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1 mediated disorder or condition in a patient, comprising administering to the patient a compound according to any of claims 1 to 7, or a composition according to any one claims 11-13.
  17. The method according to claim 16, wherein the disorder or condition is a cancer.
  18. The method according to claim 17, wherein the cancer is AML.
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TW202118756A (en) * 2019-07-29 2021-05-16 大陸商蘇州亞盛藥業有限公司 Heterocyclic compounds as bcr-abl inhibitors
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WO2021143927A1 (en) * 2020-01-19 2021-07-22 正大天晴药业集团股份有限公司 Compound acting as bcr-abl inhibitor
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