HK1184392B - Cyclopropyl dicarboxamides and analogs exhibiting anti-cancer and anti-proliferative activities - Google Patents

Description

Cyclopropyl dicarboxamides and analogs exhibiting anti-cancer and anti-proliferative activity

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional patent application No.61/329,548 entitled "cyclic pyridine chemical AND analog reactions extraction ANTI-CANCER active", filed on 29.4.2010, which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to kinase inhibitors that exhibit novel and unexpected properties for the treatment of various diseases, including hyperproliferative diseases and cancer. More particularly, the invention relates to such compounds, methods of treating diseases, and methods of synthesizing compounds. Preferably, the present compounds are used for modulating the activity of c-MET kinase, c-MET kinase polymorphs, c-MET kinase mutants or c-MET kinase fusion proteins in the treatment of mammalian diseases, especially in human hyperproliferative diseases and human cancers. In some embodiments, the compounds disclosed herein exhibit unexpected selectivity for modulating c-MET kinase activity.

Background

c-MET is a Receptor Tyrosine Kinase (RTK) located on chromosome 7p and activated by its natural ligand hepatocyte growth factor. c-MET was found to be mutated in various solid tumors (Ma, P.C. et al cancer metastasis (2003)22: 309). Mutations in the tyrosine kinase domain are associated with hereditary papillary renal cell carcinoma (Schmidt, L. et al Nat, Genet. (1997)16: 68; Schmidt, L. et al Oncogene (1999)18:2343), whereas mutations in sema and juxtamembrane domains are commonly found in small cell lung Cancer (Ma, P.C. et al Cancer Res. (2003)63: 6272). A number of activating mutations have also been found in breast cancer (Nakopoulou, et al Histopath (2000)36(4): 313). All tumor types involved in c-MET mediated growth suggest that this is a target ideally suited for modulation by specific c-MET small molecule inhibitors.

The TPR-MET oncogene is a transformed variant of the c-MET RTK and was originally identified following treatment of a human osteosarcoma Cell line transformed with the chemical carcinogen N-methyl-N' -nitro-N-nitrosoguanidine (Park, M. The TPR-MET fusion oncoprotein is the result of a chromosomal translocation that places the TPR3 locus on chromosome 1 upstream of a portion of the c-MET gene on chromosome 7 encoding only the cytoplasmic region. Studies have shown that TPR-MET is detectable in experimental cancers (e.g., Cancer (2000)88:1801, Yu, j. Constitutive activation of c-MET kinase is caused by dimerization of Mr65,000TPR-MET oncoproteins by the leucine zipper motif encoded by TPR (Zhen, Z. et al Oncogene (1994)9: 1691). TPR-MET activates the wild-type c-MET RTK and can activate crucial cell growth pathways, including the Ras pathway (Aklilu, F. et al am. J. physiol. (1996)271: E277) and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway (Ponzetto, C. et al mol. cell. biol. (1993)13: 4600). In contrast, TPR-MET is ligand independent and lacks the CBL-like SH2 domain binding site in the membrane proximal region of c-MET, and is predominantly cytoplasmic, in contrast to c-MET RTK. c-MET immunohistochemical expression appears to be associated with aberrant β -catenin expression, a hallmark feature of epithelial-to-mesenchymal transition (EMT), and provides a good prognostic and predictive factor for breast cancer patients.

In human therapy, it is desirable to provide small molecule inhibitors of protein targets within a protein family that do not cross-inhibit closely related protein family members. These closely related protein family members are often referred to as "off-targets" to distinguish them from the essential targets of interest for inhibitors, termed "on-targets". The use of small molecules that inhibit multiple protein family members while being potent against the target of interest as human therapeutics has been limited due to the unintended side effects and toxicity resulting from the inhibition of these "off-targets".

Protein kinases constitute a family of important therapeutic proteins. There are about 518 human protein kinases. While "on-target" inhibition of the desired kinase is desirable for human therapeutics, it is also desirable in many instances to provide selective kinase inhibitors that do not substantially inhibit other "off-target" kinases within the protein family. Monoclonal antibodies are one approach to providing specific inhibitors to specific kinases without inhibiting "off-target". However, the use of small molecule inhibitors to achieve this level of selectivity is neither readily nor directly available. Thus, there is a need for kinase inhibitors that are selective for particular protein kinases. It is theorized that an unexpected increase in potency or selectivity for c-MET inhibition relative to other kinases is observed in the embodiments disclosed herein.

Disclosure of Invention

The compounds described herein are useful for the treatment of mammalian cancers, particularly human cancers including, but not limited to, solid tumors, gastric cancer, melanoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, non-small cell lung cancer, breast cancer, renal cancer, cervical cancer, primary tumor site metastasis, colon cancer, myeloproliferative diseases, diseases whose etiology or progression is dependent on c-MET kinase activity or the activity of oncogenic, aberrant fusion protein and mutated forms of c-MET kinase.

In particular, compounds of formula I are disclosed for use in the treatment of the diseases described above.

Formula I

In formula I, X and F are para to each other in chemical position; x is halogen or C1-C6 alkyl; and R3 is a non-hydrogen moiety chemically positioned ortho to the nitrogen of the B ring. The compounds described herein exhibit unexpected potency for c-MET kinase inhibition and/or unexpected increased selectivity for c-MET kinase inhibition over other kinases, particularly over other so-called c-MET kinase inhibitors.

In one aspect, compounds of formula I are described:

formula I

And pharmaceutically acceptable salts, hydrates, solvates, enantiomers, stereoisomers and tautomers thereof;

wherein

X is halogen;

z1 and Z2 are independently and individually CR2 or N;

z3 is CH or N;

with the proviso that ring B is not tetrazine;

r1 is each independently and individually halogen, H, C1-C6 alkyl, branched C3-C7 alkyl, C3-C7 cycloalkyl, or-CN;

each R2 is independently and independently H, halogen, C1-C6 alkyl, or cyano;

r3 is-C (O) R4, -C (O) -C6-C10-aryl, -C (O) -C4-C6-heterocyclyl or-C (O) -C5-C6-heteroaryl, wherein

Aryl is phenyl, naphthyl, tetrahydronaphthyl, indenyl or indanyl; and

with the proviso that when R3 is-C (o) -C4-C6-heterocyclyl, the heterocyclyl does not have a bonding hand to the N-bond of-C (o);

r4 is C1-C7 alkyl, C3-C8 cycloalkyl, - (CH)₂)_P-CN、-(CH₂)_p-OR6、-(CH₂)_P-NR6(R7)、-(CH₂)_p-SO₂-C1-C6-alkyl, - (CH)₂)_p-C6-C10-aryl, - (CH)₂)_p-C5-C6-heteroaryl or- (CH)₂)_P-C4-C6-heterocyclyl, wherein

Each alkyl or alkylene group being optionally substituted by one or two C1-C6 alkyl groups; and

aryl is phenyl, naphthyl, tetrahydronaphthyl, indenyl or indanyl;

r6 and R7 are each individually and independently H, C1-C6 alkyl or C3-C8 branched alkyl;

each cycloalkyl, aryl, heteroaryl and heterocyclyl is independently represented by- (R25)_mSubstitution;

r25 is each independently and independently C1-C6 alkyl, branched C3-C8 alkyl, halogen, - (CH)₂)_m-CN、-(CH₂)_m-OR6、-(CH₂)_m-NR6(R7)、-(CH₂)_m-SO₂-C1-C6-alkyl, - (CH)₂)_m-C(O)NR6(R7)、-(CH₂)_m-C (O) -C4-C6-heterocyclyl or- (CH)₂)_m-C4-C6-heterocyclyl, wherein each alkyl or alkylene group is optionally substituted by one or two C1-C6 alkyl groups;

each m is individually and independently 0, 1,2 or 3; and

p is 1,2 or 3.

In some embodiments of the compounds of formula I, Z1 and Z2 are CR2 and Z3 is CH.

In certain embodiments, the compound is a compound of formula Ic:

formula Ic

Or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, stereoisomer or tautomer thereof, and

wherein n is 0, 1 or 2.

In certain embodiments of the compounds of formula Ic, R3 is-C (O) R4.

In other embodiments of compounds of formula Ic, R3 is-C (O) R4 and R4Is C1-C7 alkyl, C3-C8 cycloalkyl, - (CH)₂)_P-CN、-(CH₂)_p-OR6、-(CH₂)_P-NR6(R7)、-(CH₂)_p-SO₂-C1-C6-alkyl or- (CH)₂)_P-C4-C6-heterocyclyl, and wherein each alkyl or alkylene group is optionally substituted by one or two C1-C6 alkyl groups.

In some embodiments of compounds of formula Ic, R3 is-C (o) R4 and R4 is C1-C7 alkyl or C3-C8 cycloalkyl, and wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl.

In some embodiments of compounds of formula Ic, R3 is-C (O) -C6-C10-aryl, -C (O) -C4-C6-heterocyclyl, or-C (O) -C5-C6-heteroaryl.

In some embodiments of the compounds of formula I, Z1 and Z2 are CR2 and Z3 is N.

In certain embodiments, the compound of formula I is a compound of formula If,

formula If

Or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, stereoisomer or tautomer thereof, and

wherein

n is 0, 1 or 2.

In certain embodiments of the compounds of formula If, R3 is-c (o) R4.

In other embodiments of compounds of formula If, R3 is-C (O) -C6-C10-aryl, -C (O) -C4-C6-heterocyclyl, or-C (O) -C5-C6-heteroaryl.

In some embodiments of the compounds of formula I, Z1 is CR2, Z2 is N, and Z3 is CH.

In certain embodiments, the compound of formula I is a compound of formula Ij:

formula Ij

Or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, stereoisomer or tautomer thereof.

In certain embodiments of compounds of formula Ij, R3 is-c (o) R4.

In other embodiments of compounds of formula Ij, R3 is-C (o) -C6-C10-aryl, -C (o) -C4-C6-heterocyclyl, or-C (o) -C5-C6-heteroaryl.

In some embodiments of the compounds of formula I, Z1 is CR2, and Z2 and Z3 are N.

In certain embodiments, the compound of formula I is a compound of formula Im,

formula Im

Or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, stereoisomer or tautomer thereof.

In some embodiments of compounds of formula Im, R3 is-c (o) R4.

In other embodiments of compounds of formula Im, R3 is-C (O) -C6-C10-aryl, -C (O) -C4-C6-heterocyclyl, or-C (O) -C5-C6-heteroaryl.

In one embodiment, the present invention relates to a compound selected from the group consisting of: n- (4- (2-acetamidopyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2-acetamidopyridin-4-yloxy) -5-chloro-2-fluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2-acetamidopyridin-4-yloxy) -2, 5-difluorophenyl) -N' -phenylcyclopropane-1, 1-dicarboxamide; n- (4- (2- (2- (dimethylamino) acetamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2-acetamidopyrimidin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2- (cyclopropanecarboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (2, 5-difluoro-4- (2-propionamido) pyridin-4-yloxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (2, 5-difluoro-4- ((2- (2-methoxyacetamido) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (2, 5-difluoro-4- (2-isobutyramidopyridin-4-yloxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2- (2-cyanoacetamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2- (azetidine-3-carboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2- (cyclobutanecarboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; (R) -N- (2, 5-difluoro-4- ((2- (2-methoxypropionylamino) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; r) -N- (2, 5-difluoro-4- ((2- (2-hydroxypropionamido) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (2, 5-difluoro-4- ((2-pivaloylamidopyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; (S) -N- (2, 5-difluoro-4- ((2- (2-methoxypropionylamino) pyridin-4-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; (S) -1- ((4- (2, 5-difluoro-4- (1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxamido) phenoxy) pyridin-2-yl) amino) -1-oxopropan-2-yl acetate; n- (2, 5-difluoro-4- ((2- (2-fluoro-2-methylpropanamido) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide, and pharmaceutically acceptable salts, solvates, hydrates, and tautomers thereof.

In another embodiment, the present invention relates to a compound selected from the group consisting of: n- (4- (2- (cyclopropanecarboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (2, 5-difluoro-4- (2-propionamidopyridin-4-yloxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (2, 5-difluoro-4- (2-isobutyramidopyridin-4-yloxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2-acetamidopyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide.

In some embodiments, the invention includes a method of treating a disease in a mammal, wherein the disease etiology or progression is mediated at least in part by kinase activity, wherein the kinase is a wild-type form, a mutant oncogenic form, an aberrant fusion protein form, or a polymorph, comprising administering to a mammal in need thereof an effective amount of a compound of any one of claims 1-21.

In certain embodiments, the disease etiology or progression is mediated at least in part by the kinase activity of c-MET or a mutant oncogenic form, aberrant fusion protein, or polymorph thereof.

In some embodiments, the present invention relates to a pharmaceutical composition comprising a compound of any one of claims 1-21 and a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical composition further comprises an additive selected from the group consisting of an adjuvant, an excipient, a diluent, or a stabilizer.

In other embodiments, the invention relates to the treatment of cancer; gastrointestinal stromal tumors; hyperproliferative diseases; metabolic diseases; neurodegenerative diseases; or a disease characterized by angiogenesis, such as a solid tumor, melanoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, renal cancer, liver cancer, cervical cancer, primary tumor site metastasis, myeloproliferative diseases, chronic myelogenous leukemia, papillary thyroid cancer, non-small cell lung cancer, mesothelioma, hypereosinophilic syndrome, colon cancer; ocular diseases characterized by hyperproliferation leading to blindness, including retinopathy, diabetic retinopathy, age-related macular degeneration; hypereosinophilic syndrome; rheumatoid arthritis; asthma; chronic obstructive pulmonary disease; mastocytosis; or mast cell leukemia, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1-21.

In some embodiments, the compound is administered orally, parenterally, by inhalation, or subcutaneously.

The details of the invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific definitions used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Detailed Description

In this disclosure, reference is made to various patents, patent applications, and publications. The disclosures of these patents, patent applications, and publications in their entireties are hereby incorporated by reference into this disclosure in order to more fully describe the state of the art as known to those skilled in the japanese art to which this disclosure pertains. In the event that a patent, patent application, or publication is inconsistent with this disclosure, it is up to this disclosure.

For convenience, certain terms used in the specification, examples, and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Unless otherwise indicated, the initial definitions of groups or terms provided in this disclosure apply throughout this disclosure, either alone or as part of another group.

The disclosed compounds include any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts and solvates thereof, as well as crystalline polymorphic forms of the compounds of the disclosure and any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts and solvates thereof. Thus, the terms "a compound" and "compounds" as used in this disclosure refer to the disclosed compounds and any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, and solvates and crystalline polymorphs thereof.

Definition of

The term "alkyl" as used herein refers to a straight chain alkyl group, wherein the alkyl chain length is represented by a series of numbers. In exemplary embodiments, "alkyl" refers to an alkyl chain as defined above containing 1,2, 3, 4,5, or6 carbons (i.e., C1-C6 alkyl). Examples of alkyl groups include, but are not limited to: methyl, ethyl, propyl, butyl, pentyl and hexyl.

The term "branched alkyl" as used herein refers to an alkyl chain wherein there are branch points in the chain and the total number of carbons in the chain is represented by a series of numbers. In exemplary embodiments, "branched alkyl" refers to an alkyl chain as defined above containing 3, 4,5, 6, 7, or 8 carbon atoms (i.e., branched C3-C8 alkyl). Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, and tert-butyl.

The term "alkoxy" as used herein refers to-O- (alkyl), wherein "alkyl" is as defined above.

The term "branched alkoxy" as used herein refers to — O- (branched alkyl), wherein "branched alkyl" is as defined above.

The term "alkylene" as used herein refers to an alkyl moiety inserted between two other atoms. In exemplary embodiments, "alkylene" refers to an alkyl moiety as defined above containing 1,2, or 3 carbon atoms. Examples of alkylene groups include, but are not limited to, -CH₂-、-CH₂CH₂-and-CH₂CH₂CH₂-. In exemplary embodiments, the alkylene group is branched.

The term "alkynyl" as used herein refers to a carbon chain containing one carbon-carbon triple bond. In exemplary embodiments, "alkynyl" refers to carbon chains as described above that contain 2 or 3 carbon atoms (i.e., C2-C3 alkynyl). Examples of alkynyl groups include, but are not limited to, acetylene and propyne.

The term "aryl" as used herein refers to a cyclic hydrocarbon in which the rings are characterized by sharing delocalized pi electrons between ring members (aromaticity), and in which the number of ring atoms is indicated by a series of numbers. In exemplary embodiments, "aryl" refers to a cyclic hydrocarbon as described above that contains 6, 7, 8, 9, or 10 ring atoms (i.e., a C6-C10 aryl). Examples of aryl groups include, but are not limited to, benzene, naphthalene, tetralin, indene, and indane.

The term "cycloalkyl" as used herein refers to a monocyclic saturated carbocyclic ring in which the number of ring atoms is indicated by a series of numbers. In exemplary embodiments, "cycloalkyl" refers to a carbocyclic ring as defined above that contains 3, 4,5, 6, 7, or 8 ring atoms (i.e., C3-C8 cycloalkyl). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine.

The term "heterocycle" or "heterocyclyl" as used herein refers to a cyclic hydrocarbon in which at least one ring atom is O, N or S, wherein the number of ring atoms is indicated by a series of numbers. The heterocyclyl moiety as defined herein has a C or N bonding end. For example, in some embodiments, the ring N atom of a heterocyclyl group is a bonding atom to-c (o) to form an amide, a carbamate, or a urea. In exemplary embodiments, "heterocyclyl" refers to cyclic hydrocarbons containing 4,5, or6 ring atoms (i.e., C4-C6 heterocyclyl) as described above. Examples of heterocyclic groups include, but are not limited to: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, pyran, thiopyran, thiomorpholine S-oxide, thiomorpholine S-dioxide, oxazoline, tetrahydrothiophene, piperidine, tetrahydropyran, thiane, imidazolidine, oxazolidine, thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane, and dioxane.

The term "heteroaryl" as used herein refers to a cyclic hydrocarbon in which at least one ring atom is O, N or S, the ring being characterized by sharing delocalized pi electrons (aromaticity) between ring members, and wherein the number of ring atoms is indicated by a series of numbers. A heteroaryl moiety as defined herein has a C or N bonding end. For example, in some embodiments, the ring N atom of a heterocyclyl group is a bonding atom to-c (o) to form an amide, a carbamate, or a urea. In exemplary embodiments, "heteroaryl" refers to a cyclic hydrocarbon containing 5 or6 ring atoms (i.e., C5-C6 heterocyclyl) as described above. Examples of heterocyclic groups include, but are not limited to: pyrrole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine and triazine.

The term "substituted" as used herein in relation to a moiety refers to a further substituent attached to the moiety at any acceptable position on the moiety. Unless otherwise specified, moieties may be bonded through carbon, nitrogen, oxygen, sulfur, or any other acceptable atom.

The term "salt" as used herein includes the pharmaceutically acceptable salts commonly used to form alkali metal salts of the free acids as well as the addition salts used to form the free bases. The nature of the salt is not critical as long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic acids or from organic acids. Exemplary pharmaceutical Salts are disclosed in Stahl, P.H., Wermuth, C.G., Handbook of pharmaceutical Salts: Properties, Selection and Use; Verlag Helvetica Chimica acta/Wiley-VCH: Zurich,2002, the contents of which are incorporated herein by reference in their entirety. Specific non-limiting examples of inorganic acids are: hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acids. Suitable organic acids include, but are not limited to: aliphatic, alicyclic, aromatic, araliphatic and heterocyclic groups containing carboxylic and sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, methanesulfonic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylsulfamic acid, alginic acid, 3-hydroxybutyric acid, mucic acid, galacturonic acid. Suitable pharmaceutically acceptable salts of the free acids comprising the compounds disclosed herein include, but are not limited to, metal salts and organic salts. Exemplary metal salts include, but are not limited to: suitable alkali metal (group Ia), alkaline earth metal (group IIa) salts and salts of other physiologically acceptable metals. These salts can be prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Exemplary organic salts can be prepared from primary, secondary, tertiary amines, and quaternary ammonium salts, for example, tromethamine, diethylamine, tetra-N-methylammonium, N' -diphenylmethylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

The term "salt" as used herein includes the pharmaceutically acceptable salts commonly used to form alkali metal salts of the free acids as well as the addition salts used to form the free bases. The nature of the salt is not critical as long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic acids or from organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from aliphatic, alicyclic, aromatic, araliphatic and heterocyclic groups comprising carboxylic and sulphonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, methanesulfonic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylsulfamic acid, alginic acid, 3-hydroxybutyric acid, mucic acid, galacturonic acid. Suitable pharmaceutically acceptable salts of the free acids comprising the compounds disclosed herein include, but are not limited to, metal salts and organic salts. Exemplary metal salts include, but are not limited to: suitable alkali metal (group Ia), alkaline earth metal (group IIa) salts and other physiologically acceptable salts. These salts can be prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Exemplary organic salts can be prepared from primary, secondary, tertiary amines, and quaternary ammonium salts, for example, tromethamine, diethylamine, tetra-N-methylammonium, N' -diphenylmethylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

The term "administering" as used herein refers to the direct administration of a compound or a pharmaceutically acceptable salt of a compound or composition to a subject.

The term "carrier" as used herein encompasses carriers, excipients and diluents, and refers to materials, compositions or excipients, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials, involved in carrying or transporting a pharmaceutical formulation from one organ or site of the body to another organ or site of the body.

Unless otherwise indicated, the term "disorder" is used in this disclosure to mean and is used interchangeably with the term disease, condition, or disorder.

The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound that, when administered to a subject, is capable of alleviating the symptoms of a disorder in the subject. The actual amount comprising an "effective amount" and a "therapeutically effective amount" varies depending on the number of conditions including, but not limited to: the particular condition to be treated; severity of the condition; the size and health of the patient; and the route of administration. Suitable amounts can be readily determined by the skilled practitioner using methods known in the medical arts.

The terms "isolated" and "purified" as used herein refer to components that are separated from a reaction mixture or other components of natural origin. In certain embodiments, an isolate comprises at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the compound or a pharmaceutically acceptable salt of the compound by weight of the isolate.

The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used in this disclosure, the term "subject" includes, but is not limited to, a human or an animal. Exemplary animals include, but are not limited to, mammals, such as mice, rats, guinea pigs, dogs, cats, horses, cows, pigs, monkeys, chimpanzees, baboons, or macaques.

The term "treating" with respect to a subject as used herein refers to ameliorating at least one symptom of a disorder in the subject. The treatment may be a cure, amelioration, or at least partial alleviation of the condition.

As herein describedThe term "hydrate" as used refers to a compound disclosed herein that is associated with water in molecular form, i.e., wherein the H-OH bond is not split and can be represented, for example, by the formula R · H₂O, wherein R is a compound disclosed herein. A given compound may form more than one hydrate, including, for example, monohydrate (R.H)₂O), dihydrate (R.2H)₂O), trihydrate (R.3H)₂O), and the like.

The term "solvate" as used herein refers to a compound disclosed herein that is molecularly associated with a solvent, i.e., wherein the solvent is coordinately bound, and can be represented, for example, by the formula R · (solvent), wherein R is a compound disclosed herein. A given compound may form more than one solvate, including, for example, a single solvate (R.cndot.) or a multiple solvate (R.cndot. (solvent) where n is greater than 1) including, for example, a di-solvate (R.cndot. (solvent)), a tri-solvate (R.cndot. (solvent)), and the like, or a semi-solvate, such as R.cndot. (solvent)) R.cndot. (solvent), R.cndot. (solvent) and the like, where n is an integer.

The term "acid hydrate" as used herein refers to a complex that can be formed by associating a compound having one or more basic moieties with at least one compound having one or more acidic moieties or by associating a compound having one or more acidic moieties with at least one compound having one or more basic moieties, said complex further associating with water molecules to form a hydrate, wherein the hydrate is as previously defined and R represents a complex as described herein above.

The structural, chemical and stereochemical definitions are widely adopted by the IUPAC recommendation (IUPAC Recommendations), and more specifically from the glossary of terms used in Physical organic chemistry (IUPAC recommendation 1994) as outlined by Muller, P.Pure Appl.chem.1994,66, p.1077. 2224 and the basic stereochemical term Bass (IUPAC recommendation 1996) as outlined by Moss, G.P.Pure Appl.chem.1996,68, p.2193. 2222.

Atropisomers are defined as a subclass of conformers that can be separated into individual chemical species and that result from hindered rotation about a single bond.

Regioisomers or structural isomers are defined as isomers comprising different arrangements of the same atoms.

Enantiomers are defined as a pair of sub-entities that are mirror images of each other and that do not overlap.

Diastereomers or diastereomers are defined as stereoisomers that differ from enantiomers. Diastereomers or diastereomers are mirror image unrelated stereoisomers. Diastereomers are characterized by differences in physical properties and by some differences in chemical behavior with respect to achiral and chiral agents.

The term "tautomer" as used herein refers to a compound prepared by the phenomenon of transfer of a proton of one atom of a molecule to another atom. See March, Advanced Organic Chemistry: Reactions, mechanics and Structures, fourth edition, John Wiley & Sons, pages 69-74 (1992). Tautomers are defined as isomers of the general formula:

wherein isomers (referred to as tautomers) are readily interconvertible; the atom linking group X, Y and Z is typically any of C, H, O or S, and G is a group that becomes an ionophore or nucleofuge upon isomerization. Most often, when the ionizer is H⁺And is also referred to as "proton shift". Tautomers are defined as isomers resulting from tautomerism independent of whether the isomers can be separated or not.

ChemDraw version 8.0 or 10(Cambridge Soft Corporation, Cambridge, MA) was used to name the structure.

The following abbreviations are used in this disclosure and have the following definitions: ADP is adenosine diphosphate; ATP is adenosine triphosphate; dba is diphenylmethanone acetone; DIEA is N, N-diisopropylethylamine; DMA is N, N-dimethylacetamide; DMF is N, N-dimethylformamide; DMSO is dimethyl sulfoxide; DTT is dithiothreitol; EGTA is ethylene glycol tetraacetic acid; ESI is electrospray ionization; GST is glutathione S-transferase; "h" is one or more hours; HATU is 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate; HEPES is 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid; HPLC is high pressure (high performance) liquid chromatography; IC (integrated circuit)₅₀Is half maximal inhibitory concentration; MS is mass spectrum; min is minutes; NADH is nicotinamide adenine dinucleotide; NMR is nuclear magnetic resonance; PBS is phosphate buffered saline; RT is room temperature; THF is tetrahydrofuran; tris is Tris (hydroxymethyl) aminomethane; and xantphos is 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene.

Compound (I)

In one aspect, compounds of formula I are described:

formula I

And pharmaceutically acceptable salts, hydrates, solvates, enantiomers, stereoisomers and tautomers thereof;

wherein

X, B, Z1, Z2, Z3, R1, R2, R3, R4, R6, R7, R25, m, n and p are as defined above for formula I; and

the heterocyclyl and heteroaryl each individually and independently have a C or N bonding end.

In some embodiments, the ring N atom of the heterocyclyl group is a bonding atom to-c (o) to form an amide, a carbamate, or a urea. In other embodiments, the ring N atom of the heteroaryl group is a bonding atom to-c (o) to form an amide, a carbamate, or a urea.

In some embodiments, the compound of formula I is a compound of formula Ib:

formula Ib

And pharmaceutically acceptable salts, hydrates, solvates, enantiomers, stereoisomers and tautomers thereof;

wherein

X, R1, R2, R3, R4, R6, R7, R25, m, n and p are as defined above for formula I; and

n is 0, 1 or 2;

in some embodiments, the compound of formula I is a compound of formula Ic:

formula Ic

And pharmaceutically acceptable salts, hydrates, solvates, enantiomers, stereoisomers and tautomers thereof;

wherein

R2, R3, R4, R6, R7, R25, m, n and p are as defined above for formula Ib.

In some embodiments, the compound of formula I is a compound of formula Ie:

formula Ie

And pharmaceutically acceptable salts, hydrates, solvates, enantiomers, stereoisomers and tautomers thereof;

wherein

X, R1, R2, R3, R4, R6, R7, R25, m, n and p are as defined above for formula Ib.

In some embodiments, the compound of formula I is a compound of formula If:

formula If

And pharmaceutically acceptable salts, hydrates, solvates, enantiomers, stereoisomers and tautomers thereof;

wherein

R2, R3, R4, R6, R7, R25, m, n and p are as defined above for formula Ib.

In some embodiments, the compound of formula I is a compound of formula Ih:

formula Ih

And pharmaceutically acceptable salts, hydrates, solvates, enantiomers, stereoisomers and tautomers thereof;

wherein

X, R1, R2, R3, R4, R6, R7, R25, m, n and p are as defined above for formula I.

In some embodiments, the compound of formula I is a compound of formula Ij:

formula Ij

And pharmaceutically acceptable salts, hydrates, solvates, enantiomers, stereoisomers and tautomers thereof;

wherein

R2, R3, R4, R6, R7, R25, m, n and p are as defined above for formula I.

In some embodiments, the compound of formula I is a compound of formula Il:

formula Il

And pharmaceutically acceptable salts, hydrates, solvates, enantiomers, stereoisomers and tautomers thereof;

wherein

X, R1, R2, R3, R4, R6, R7, R25, m, n and p are as defined above for formula I.

In some embodiments, the compound of formula I is a compound of formula Im:

formula Im

And pharmaceutically acceptable salts, hydrates, solvates, enantiomers, stereoisomers and tautomers thereof;

wherein

R2, R3, R4, R6, R7, R25, m, n and p are as defined above for formula I.

The following embodiments describe formula I, formula Ib, formula Ie, formula Ih and formula Il.

In some embodiments, X is halogen. In other embodiments, X is F or Cl. In a further embodiment, X is F.

In some embodiments, each R1 is individually and independently halogen. In other embodiments, each R1 is independently and independently F or Cl. In further embodiments, each R1 is F.

In some embodiments, m is 1 and R1 is halogen. In other embodiments, m is 1 and R1 is F or Cl. In a further embodiment, m is 1 and R1 is F.

In some embodiments, X and each R1 are independently and individually halogen. In other embodiments, X and each R1 is individually and independently F or Cl. In a further embodiment, X and each R1 is F.

In some embodiments, m is 1 and X and each R1 is independently and individually halogen. In other embodiments, m is 1 and X and each R1 is individually and independently F or Cl. In a further embodiment, m is 1 and X and each R1 is F.

The following embodiments describe formula I, formula Ib, formula Ic, formula Ie, formula If, formula Ih, formula Ij, formula Il and formula Im.

In some embodiments, R3 is-C (O) R4 and R4 is C1-C7 alkyl, C3-C8 cycloalkyl, - (CH)₂)_p-CN、-(CH₂)_p-OR6、-(CH₂)_P-NR6(R7) or- (CH)₂)_p-C4-C6-heterocyclyl, wherein each alkyl or alkylene group is optionally substituted by one or two C1-C6 alkyl groups. In further embodiments, one alkyl or alkylene group is substituted with one C1-C6 alkyl group. In yet a further embodiment, one alkyl or alkylene groupSubstituted by a Cl-alkyl group.

In some embodiments, R3 is-C (o) -C6-C10-aryl, -C (o) -C4-C6-heterocyclyl, or-C (o) -C5-C6-heteroaryl.

In illustrative embodiments, the compounds disclosed herein are as follows:

use of

The compounds described herein are useful for the treatment of mammalian cancers and in particular human cancers including, but not limited to, solid tumors, gastric cancer, melanoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, non-small cell lung cancer, breast cancer, renal cancer, cervical cancer, primary tumor site metastases, colon cancer, myeloproliferative diseases, diseases whose etiology or progression is dependent on c-MET kinase activity or oncogenic, aberrant fusion protein and mutated forms of c-MET kinase.

Administration of the Compounds

In some embodiments, the compound is administered by a route selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.

Method of treatment

The methods of the present disclosure further comprise treating an individual having a disorder selected from: cancer, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases or diseases characterized by angiogenesis. These methods comprise administering to these individuals the compounds disclosed herein, and particularly those of part 1, including but not limited to solid tumors; malignant melanoma; a glioblastoma; ovarian cancer; pancreatic cancer; prostate cancer; lung cancer; breast cancer; kidney cancer; liver cancer; cervical cancer; primary tumor site metastasis; myeloproliferative diseases; chronic myelogenous leukemia; leukemia; papillary thyroid carcinoma; non-small cell lung cancer; mesothelioma; hypereosinophilic syndrome; gastrointestinal stromal tumors; colon cancer; ocular diseases characterized by hyperproliferation leading to blindness, including various retinopathies, diabetic retinopathy and age-related macular degeneration; and hypereosinophilic syndrome; rheumatoid arthritis; asthma; chronic obstructive pulmonary disease; mastocytosis; mast cell leukemia; diseases caused by c-MET kinase, oncogenic forms thereof, abnormal fusion proteins thereof, and polymorphs thereof. The method of administration is not critical and may be selected from oral, parenteral, inhalation and subcutaneous.

Pharmaceutical preparation

The compounds disclosed herein may form part of a pharmaceutical composition by combining one or more of these compounds with a pharmaceutically acceptable carrier. In addition, the composition may comprise additives selected from adjuvants, excipients, diluents and stabilizers.

Preparation method

The compounds of the present invention can be obtained by the general synthetic methods shown in the following schemes and the accompanying examples.

The compounds of the invention are prepared in a stepwise manner as shown in scheme 11. From cyclopropane-1, 1-dicarboxylic acids2Initially, amines are used in forming the new amide bond3Via standard peptide coupling chemistry familiar to those skilled in the art to produce intermediates4. Alternatively, it is appreciated that in this case, as well as in other cases below, such as in2The carboxylic acid moieties present in (a) are masked by esters or activated as acid halides, anhydrides, mixed anhydrides; or as an activated ester. In the case of activated acid derivatives, it is understood that they react with amines3Are combined to form4Previously, these compounds were optionally isolated as discrete intermediates. By peptide coupling conditions or by activation of acid intermediates, followed by4With aniline5Coupling to give the desired formula1The compound of (1). Using a similar approach, in some embodiments, carboxylic acids2Also first with aniline5Coupling to give intermediates6Which is then reversed with3Coupling to give the desired Compound1。

Scheme 1

Non-limiting examples of the process described in scheme 1 are shown below. Scheme 2 shows compounds10By the usual sequence2→4→1(scheme 1) general formula1(wherein R1 is F, Z1, Z2, and Z3 is CH and R3 is-C (O) CH₃) Examples of (3). Thus, 1, 1-cyclopropane bis-carboxylic acid is shown below2With amines7(generally amines)3Examples of (b) to provide an amide/acid8Intermediates in general4Examples of (3). The conversion conditions include in situ activation of the diacid (bis-acid) by treatment with thionyl chloride in the presence of a tertiary base such as triethylamine2Subsequently with amines7And (4) reacting. In the presence of a peptide coupling agent8With amines9(intermediates in general)5Examples of (b) further reacted to provide the di-amide10. Coupling agents for subsequent transformations included TBTU (O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate), PyBOP (benzotriazol-1-yloxy hexafluorophosphate) trispyrrolidinyl phosphonium), EDC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride), and BOP-C1 (bis (2-oxo-3-oxazolidinyl) phosphonyl chloride).

Scheme 2

To10Examples of alternative routes of (1), formula1An example of (b) is shown in scheme 3. In this case, the preparation starts with11Wherein the dicarboxylic acid2One carboxylic acid moiety of (a) is protected as a methyl ester. Acid was reacted using the conditions described above (scheme 1)11With aniline9Coupling to give the methyl ester12. The esters are reacted using standard conditions (e.g., aqueous LiOH)12Saponification followed by treatment with thionyl chloride to yield an activated acid chloride intermediate13. Acid chlorides in the presence of bases such as triethylamine or Hunig's base13Readily react with amines7Reacting to produce a sample10。

Scheme 3

The general formulae used in the present invention are prepared by standard methods familiar to the person skilled in the art3Amines of (4). A number of non-limiting examples are shown in the following schemes. Reacting phenols in which LG is a leaving group such as halide or sulfonate14And benzamide15In the presence of a base such as potassium tert-butoxide and a polar aprotic solvent at elevated temperatures (e.g., 100 ℃) to produce16(scheme 4). Protection using suitable Protecting Groups (PG) familiar to the person skilled in the art, such as tert-Butoxycarbonyl (BOC)16Aniline NH of₂Followed by Hofmann rearrangement conditions to result in17Is performed. Using R3-LG (18) Will be provided with17Acylation followed by removal of the protecting group to give the amine3. In one example, the reagent R3-LG (L: (L))18) Is carried out as described above using a standard peptide coupling agent with17Wherein LG is OH. Alternatively, the reagent R3-LG (18) Is prepared by reacting with an amine17To obtain3Such as an acid halide (wherein LG is halo).

Scheme 4

A non-limiting example of this synthetic route is shown in scheme 5. Thus, phenol is made by heating under alkaline conditions14With 4-chloropyridyl amides19(intermediate)15See scheme 4) wherein Z1, Z2 and Z3 are CH and LG is Cl) to produce20. Protection with BOC groups using conditions familiar to those skilled in the art20To obtain an aniline moiety of21. Amide 21 is further subjected to Hofmann rearrangement to give aminopyridines22. Conditions for the hofmann rearrangement include bromine in aqueous KOH or the addition of an oxidizing agent, for example lead tetraacetate or a hypervalent iodine reagent such as bis (trifluoroacetyl) iodobenzene in pyridine. Subsequently in a solution of pyridine22Acylation with acetyl chloride (an example of R3-LG, wherein LG is chloride) to give23. Removal of the BOC protecting group in HCl solution to give the amine7Amines of3Wherein Z1, Z2 and Z3 are CH and R3 is-C (O) CH₃。

Scheme 5

Optionally, a revised version of the pathway shown in scenario 4 is shown in scenario 6. See above, Synthesis16Thereafter, peptide coupling chemistry or carboxylic acids are used6With a carboxylic acid6Combine to produce24. Make it24Subjected to Hoffmann rearrangement conditions to produce25Then using an activated acid18Acylating it to give the formula1The compound of (1).

Scheme 6

By passing26Also obtained is the general formula3Wherein Y is a typical leaving group in a transition metal mediated coupling reaction (e.g., chloride, bromide, or triflate) (scheme 7). Using a catalytic amount of Pd (OAc) in the presence of cesium carbonate at an elevated temperature of between 45 ℃ and 110 ℃₂Or Pd₂(dba)₃And xantphos to work up in aprotic solvents26And amides27To produce intermediates3(see Buchwald et al, org. Lett. (2000),2(8): 1101). Similarly, the method described in scheme 3 was used26And6to synthesize intermediate28Followed by catalytic palladium and xanthphos (see above) with27React to produce formula1The compound of (1).

Scheme 7

Synthesis of amines in various ways including those shown in the following non-limiting examples26. As shown in scheme 8, the aminophenol is added after a base such as potassium tert-butoxide in DMA solution at an elevated temperature between 80 ℃ and 100 ℃14And29(wherein LG is a leaving group, such as a halide or sulfonate, in a nucleophilic substitution reaction).

Scheme 8

By 1-fluoro-4-nitrobenzene intermediates30(scheme 9) also obtaining the usual amines26. At a temperature between 0 ℃ and 80 ℃ in the presence of a base such as sodium hydride30And31coupling of (3). The resulting nitro intermediate is then reacted using various methods familiar to those skilled in the art32Reduction to give amines26。

Scheme 9

The following non-limiting example of scheme 9 is shown for synthesis36，26Wherein X is F, Y is Cl, and Z1, Z2 and Z3 are CH (scheme)10). 1,2, 4-trifluoro-5-nitrobenzene (b) at 0 ℃33) 2-Chloropyridin-4-ol added to DMF (34) And sodium hydride solution to produce nitro intermediates35. Then at RT in the presence of zinc powder and ammonium chloride in a solution of methanol and THF35Reduction of the nitro moiety to give the amine36。

Scheme 10

From intermediates prepared in scheme 1036Initially, a non-limiting example of scenario 7 is shown in scenario 11. Thus, in the presence of triethylamine,36is easy to react with acid chloride13(see scheme 3) reaction to produce chloropyridines37. Acetamide (R3-NH) was then used in the presence of catalytic amounts of palladium acetate and xanthphos₂ 27Wherein R3 is acetyl) and cesium carbonate, and reacting the mixture with a pyridine chloride37Is converted into38，1In which R1 is F, X is F, Z1, Z2 and Z3 are CH and R3 is-C (O) CH₃。

Scheme 11

Using the synthetic procedures and methods described herein and methods known to those skilled in the art, the following compounds were prepared: n- (4- (2-acetamidopyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2-acetamidopyridin-4-yloxy) -5-chloro-2-fluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2-acetamidopyridin-4-yloxy) -2, 5-difluorophenyl) -N' -phenylcyclopropane-1, 1-dicarboxamide; n- (4- (2- (2- (dimethylamino) acetamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2-acetamidopyrimidin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2- (cyclopropanecarboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (2, 5-difluoro-4- (2-propionamidopyridin-4-yloxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (2, 5-difluoro-4- ((2- (2-methoxyacetamido) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (2, 5-difluoro-4- (2-isobutyramidopyridin-4-yloxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2- (2-cyanoacetamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2- (azetidine-3-carboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (4- (2- (cyclobutanecarboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; (R) -N- (2, 5-difluoro-4- ((2- (2-methoxypropionylamino) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; r) -N- (2, 5-difluoro-4- ((2- (2-hydroxypropionylamino) pyridin-4-yl) oxy) phenyl) -N' (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; n- (2, 5-difluoro-4- ((2-pivaloylamidopyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; (S) -N- (2, 5-difluoro-4- ((2- (2-methoxypropionylamino) pyridin-4-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; (S) -1- ((4- (2, 5-difluoro-4- (1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxamido) phenoxy) pyridin-2-yl) amino) -1-oxopropan-2-yl acetate; and N- (2, 5-difluoro-4- ((2- (2-fluoro-2-methylpropionamido) pyridin-4-yl) oxy) phenyl) -N' (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide.

Examples

The disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the disclosure to the particular procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and are not intended to limit the scope of the disclosure. It is further understood that various other embodiments, modifications, and equivalents may be resorted to as will occur to those skilled in the art without departing from the spirit of the disclosure and/or the scope of the appended claims.

Sample A1: sodium hydride (60 wt% in mineral oil) (3.08g,77mmol) was placed in a 500mL argon-filled round bottom flask. DMF (140mL) was added and the mixture was cooled in an ice bath. 2-chloro-4-hydroxypyridine (7.68g,59.3mmol) was then added slowly over 45 minutes. After the addition of hydroxypyridine was complete, 2,4, 5-trifluoronitrobenzene (10.5g,59.3mmol) was added as a solution in DMF (29 mL). The mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to remove a large amount of DMF in the mixture, and then partitioned between ethyl acetate (300mL) and 10% aqueous lithium chloride (150 mL). The precipitate formed was removed by suction filtration and the layers were separated. The organic layer was washed with additional 10% aqueous lithium chloride (2 × 150mL), saturated aqueous sodium bicarbonate (150mL), and brine (150 mL). The organic layer was dried over magnesium sulfate and evaporated to give a dark red solid which was purified by silica gel chromatography (10 to 30% ethyl acetate/hexanes) to give 2-chloro-4- (2, 5-difluoro-4-nitrophenoxy) pyridine (13.56g,80% yield) as a yellow solid.¹H NMR(400MHz,DMSO-d₆):8.45(dd,1H),8.39(d,1H),7.87(dd,1H),7.39(d,1H),7.24(dd,1H);MS(ESI)m/z:287.0(M+H⁺)。

2-chloro-4- (2, 5-difluoro-4-nitrophenoxy) pyridine (13.06g,45.6mmol) was dissolved in methanol (228mL) and THF (228mL), then cooled in an ice bath. Ammonium chloride (24.37g,456mmol) followed by zinc powder (29.8g,456mmol) was added and the mixture was stirred in an ice bath for 30 min. After 30 minutes, the ice bath was removed and the reaction mixture was warmed to room temperature. After stirring for a further hour, the mixture is passedFiltered and washed thoroughly with methanol. The filtrate was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (200mL) and water (100 mL). Additional water (50mL) and brine (100mL) were usedThe organic layer was washed, dried over magnesium sulfate, and concentrated to give 4- (2-chloropyridin-4-yloxy) -2, 5-difluoroaniline (11.60g,99% yield) as a light brown solid. MS (ESI) M/z 257.0(M + H)⁺)。

Sample A2: 2-chloro-4-hydroxypyridine (0.319g,2.460mmol) was dissolved in DMF (10mL) under argon and cooled to-15 ℃. Sodium hydride (60% in mineral oil) (0.148g,3.69mmol) was added slowly and the mixture was stirred for 15 minutes. 5-chloro-2, 4-difluoronitrobenzene (0.5g,2.58mmol) was then added all at once as a solution in DMF (2 mL). The reaction mixture was stirred at-15 ℃ for 1 hour, then additional 5-chloro-2, 4-difluoronitrobenzene (0.075g) was added. The mixture was stirred at-15 ℃ for an additional 15 hours, then warmed to room temperature and diluted with ethyl acetate (100mL), washed with 10% aqueous lithium chloride (3 × 75mL) and brine (75 mL). The organic layer was dried over magnesium sulfate and evaporated to give an orange oil, which was then purified by silica gel chromatography (0 to 30% ethyl acetate/hexanes) to give 2-chloro-4- (2-chloro-5-fluoro-4-nitrophenoxy) pyridine (0.64g,86% yield) as a light yellow oil.¹H NMR(400MHz,DMSO-d₆):8.57(dd,1H),8.36(dd,1H),7.87(dd,1H),7.32(dd,1H),7.19(m,1H);MS(ESI)m/z:303.0(M+H⁺)。

2-chloro-4- (2-chloro-5-fluoro-4-nitrophenoxy) pyridine (0.64g,2.112mmol) was dissolved in methanol (50mL) and THF (50.0 mL). Ammonium chloride (1.130g,21.12mmol) followed by zinc dust (1.381g,21.12mmol) was added. The suspension was stirred at room temperature for 3 hours and then passedFiltered and evaporated to give a brown solid which was then partitioned between ethyl acetate and a 4:1 mixture of THF (150mL) and water (75 mL). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give 5-chloro-4- (2-chloropyridin-4-yloxy) -2-fluoroaniline (0.505g,88% yield) as a dark brown oil. MS (ESI) M/z 273.0(M + H)⁺)。

Sample A3:4 in acetic acid (200mL) was added at 80 ℃,a solution of 6-dichloro-pyrimidin-2-ylamine (5g,30mmol) and acetyl chloride (4.7g,60mmol) was stirred under nitrogen overnight. The solution was cooled to RT and water (150mL) was added. The mixture was extracted with ethyl acetate (3 × 150mL), then the combined organics were washed with brine, dried over sodium sulfate and concentrated to give N- (4, 6-dichloro-pyrimidin-2-yl) -acetamide (5.0g,79% yield).

A solution of 4-amino-2, 5-difluoro-phenol (3.5g,24mmol), N- (4, 6-dichloro-pyrimidin-2-yl) -acetamide (5.30g,24mmol) and potassium carbonate (3.4g,24mmol) in DMF (100mL) was stirred under nitrogen overnight at 50 ℃. After cooling to room temperature, the reaction mixture was suspended in water (300mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography (15% -20% ethyl acetate in petroleum ether) to give N- [4- (4-amino-2, 5-difluoro-phenoxy) -6-chloro-pyrimidin-2-yl]-acetamide (3.3g,44% yield) as a white solid.¹HNMR(400MHz,DMSO-d₆):10.72(s,1H),7.20-7.24(dd,J=11.2Hz,J＝7.6Hz,1H),7.00(s,1H),6.64(dd,J=12.0Hz,J=8.4Hz,1H),5.48(s,2H),2.03(s,3H)。

N- [4- (4-amino-2, 5-difluoro-phenoxy) -6-chloro-pyrimidin-2-yl in methanol (100mL) was reacted at 15 deg.C]-mixture of acetamide (3.3g,10.5mmol) and palladium on carbon (1.0g,10%) in H₂Stirring for 4h under (1 atm). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give N- [4- (4-amino-2, 5-difluoro-phenoxy) -pyrimidin-2-yl]-acetamide (2.4g,82% yield) as a pale yellow solid.¹HNMR(400MHz,DMSO-d₆):10.37(s,1H),8.44(d,J=5.7Hz,1H),7.15(dd,J=11.4Hz,J＝4.8Hz,1H)6.71(d,J＝5.7Hz,1H),6.65(dd,J=12.3Hz,J=8.4Hz,1H),5.40(s,2H),1.99(s,3H);MS(ESI)m/z:281.2[M+H]⁺。

Sample B1: cyclopropane-1, 1-dicarboxylic acid monomethyl ester (2g,13.88mmol) was dissolved in DMF (28mL) and 4-fluoroaniline (1.999mL,20.82mmol) was added followed by diisopropylethylamine (12.12mL,69.4mmol) and O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (8.91g,27.8 mmol). Will be provided withThe mixture was stirred at room temperature for 15 hours, then diluted with ethyl acetate (200mL) and washed with 10% aqueous lithium chloride (3 × 100mL) and brine (100 mL). The organic layer was dried over magnesium sulfate and evaporated to give a crude brown solid. It was purified by silica gel chromatography (0 to 20% ethyl acetate/hexanes) to give methyl 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylate (3.28g,99% yield) as a pale yellow solid.¹H NMR(400MHz,DMSO-d₆):10.32(s,1H),7.60(m,2H),7.12(m,2H),3.66(s,3H),1.38(m,4H);MS(ESI)m/z:238.1(M+H⁺)。

Methyl 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylate (3.28g,14.00mmol) was dissolved in THF (23.34mL), water (11.67mL) was added followed by lithium hydroxide monohydrate (1.763g,42.0mmol), and the mixture was stirred at room temperature for 30 minutes. After this time, THF was removed under reduced pressure, and then the pH of the aqueous layer was adjusted to-5 using 2M HCl while the solution was cooled in an ice bath. The precipitate formed was dissolved in ethyl acetate (125mL) and the layers were separated. The organic layer was washed with water (100mL) and brine (100mL) and then dried over magnesium sulfate. The solvent was evaporated to give 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylic acid (2.952g,94% yield) as a beige powder.¹H NMR(400MHz,DMSO-d₆) 13.06 (width s,1H),10.56(s,1H),7.60(M,2H),7.12(M,2H),1.39(s,4H), MS (ESI) M/z 224.1(M + H)⁺)。

1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylic acid (1.484g,6.65mmol) was dissolved in thionyl chloride (14mL,192mmol) at 60 ℃. The reaction mixture was stirred under argon for 30 minutes, then the solution was cooled to room temperature and toluene (10mL) was added. The mixture was concentrated under reduced pressure. Additional toluene (10mL) was added and the mixture was concentrated again. This was repeated twice. The off-white solid obtained, 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarbonyl chloride, was used immediately in the next step without purification, giving 100% yield. MS (ESI) M/z (methanol quenching) 238.1(M + H)⁺)。

Sample B2: dissolving monomethyl cyclopropane-1, 1-dicarboxylate (0.4g,2.78mmol) in DMF(5.55mL), then aniline (0.380mL,4.16mmol) was added followed by diisopropylethylamine (2.424mL,13.88mmol) and O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (1.782g,5.55 mmol). The reaction mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate (70mL) and washed with 10% aqueous lithium chloride (3 × 40mL), saturated aqueous ammonium chloride (40mL), saturated aqueous sodium bicarbonate (40mL) and brine (40 mL). The organic layer was dried over magnesium sulfate and evaporated to give a dark brown oil. It was purified by silica gel chromatography (0 to 20% ethyl acetate/hexanes) to give methyl 1- (phenylcarbamoyl) cyclopropanecarboxylate (0.607g,100% yield) as a pale pink solid.¹H NMR(400MHz,DMSO-d₆):10.29(s,1H),7.58(d,2H),7.28(t,2H),7.04(t,1H),3.66(s,3H),1.37(m,4H);MS(ESI)m/z:220.1(M+H⁺)。

Methyl 1- (phenylcarbamoyl) cyclopropanecarboxylate (0.607g,2.77mmol) was dissolved in a mixture of THF (3.5mL) and water (3.50mL), lithium hydroxide monohydrate (0.349g,8.31mmol) was added, and the mixture was stirred at room temperature for 1 hour. THF was removed under reduced pressure, then additional water (20mL) was added. The solution was acidified to pH 4 using 2M HCl, then the precipitated beige solid was collected by suction filtration and washed with additional water to give 1- (phenylcarbamoyl) cyclopropanecarboxylic acid (0.482g,85% yield). MS (ESI) M/z 206.0(M + H)⁺)。

1- (phenylcarbamoyl) cyclopropanecarboxylic acid (0.115g,0.559mmol) was dissolved in thionyl chloride (1.224mL,16.77mmol) and heated to 60 ℃ under argon. After 1 hour, the reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. Toluene (2mL) was added and evaporated three times and the remaining light pink oil, 1- (phenylcarbamoyl) cyclopropanecarbonyl chloride, was used immediately in the next step to give 100% yield. MS (ESI) M/z (methanol quenching) 220.1(M + H)⁺)。

Example 1 (Compound D): will be provided withSample A1(2.136g,8.32mmol) was dissolved inDried THF (63mL) was then added triethylamine (1.508mL,10.82 mmol). To this solution was added dry THF (20mL)Sample B1(2.414g,9.99 mmol). The mixture was stirred at room temperature for 30 minutes. Triethylamine hydrochloride was removed from the reaction mixture by suction filtration. The filtrate was evaporated to give an orange oil which was chromatographed on silica gel (10% to 50% ethyl acetate/hexanes) to give N- (4- (2-chloropyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (3.819g,99% yield) as an opalescent solid.¹H NMR(400MHz,DMSO-d₆):11.13(s,1H),9.73(s,1H),8.30(d,1H),8.13(dd,1H),7.57(m,3H),7.16(m,3H),7.02(dd,1H),1.64(m,2H),1.57(m,2H);MS(ESI)m/z:462.1(M+H⁺)。

N- (4- (2-chloropyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (3.819g,8.27mmol), acetamide (2.442g,41.3mmol), cesium carbonate (4.04g,12.40mmol) and xanthphos (0.469g,0.810mmol) were stirred in dry dioxane (59.1mL) while bubbling argon through the mixture for 15 minutes. After this time, palladium acetate (0.139g,0.620mmol) was added and argon was bubbled through the solution for an additional 10 minutes. The round bottom flask was then connected to a reflux condenser, filled with argon and gradually heated from room temperature to 100 ℃ under bubbling argon. After 3.5 hours, the reaction mixture was cooled to room temperature at 100 ℃. The reaction mixture was diluted with a 4:1 mixture of ethyl acetate and THF (300mL) and water (100 mL). The pale yellow solid was removed by suction filtration and discarded. The organic layer was separated from the aqueous layer and washed with brine (200 mL). In addition, the aqueous layer was back-extracted with ethyl acetate/THF mixture (100mL), and the mixture was also washed with brine (50 mL). The combined organic layers were dried over magnesium sulfate and evaporated to give a peach-red oil. It was stirred in dichloromethane (50mL) for 1.5 h, the white solid formed was collected by suction filtration and washed with more dichloromethane to give N- (4- (2-acetamidopyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (3.328g,83% yield).¹HNMR(400MHz,DMSO-d₆):11.00(s,1H),10.59(s,1H),9.79(s,1H),8.19(d,1H),8.07(dd,1H),7.65(d,1H),7.57(m,3H),7.16(m,2H),6.71(dd,1H),2.02(s,3H),1.62(m,2H),1.57(m,2H);MS(ESI)m/z:485.1(M+H⁺)。

Example 2: to the direction ofSample B1(0.169g,0.699mmol) in dry THF (5.38mL)Sample A2(0.147g,0.538mmol) and triethylamine (0.098mL,0.700 mmol). The mixture was stirred at room temperature under argon for 20 minutes. The reaction mixture was then filtered through a filter (frit) to remove solid triethylamine hydrochloride salt that had precipitated. The filtrate was concentrated under reduced pressure to give a light orange oil which was purified by silica gel chromatography (0 to 50% ethyl acetate/hexanes) to give N- (5-chloro-4- (2-chloropyridin-4-yloxy) -2-fluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (0.203g,79% yield) as a clear viscous oil.¹H NMR(400MHz,DMSO-d₆):11.04(s,1H),9.77(s,1H),8.30(m,2H),7.58(m,3H),7.16(t,2H),7.07(d,1H),6.96(dd,1H),1.63(m,2H),1.56(m,2H);MS(ESI)m/z:478.1(M+H⁺)。

N- (5-chloro-4- (2-chloropyridin-4-yloxy) -2-fluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (0.200g,0.418mmol), acetamide (0.124g,2.091mmol), cesium carbonate (0.136g,0.418mmol) and xanthphos (0.017g,0.029mmol) were dissolved in dry dioxane (3mL) in a 25mL round bottom flask. Argon was bubbled through the reaction mixture for 5 minutes, then palladium acetate (4.69mg,0.021mmol) was added. The mixture was degassed again for five minutes, and then the reaction flask was connected to a reflux condenser. The system was filled with argon and then heated at 100 ℃ under bubbling argon for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (30mL) and a 4:1 mixture of ethyl acetate and THF (150 mL). The layers were separated and the aqueous layer was washed with additional ethyl acetate/THF solution. The organic layers were combined and concentrated to give a viscous orange oil. After addition of methanol (3mL), a fine, opalescent precipitate formed which was collected by suction filtration and then washed with a small amount of dichloromethane to give an N- (4- (2-acetamidopyridin-4-yloxy) -5-chloro-2-fluorophenyl) -N' - (4-fluorophenyl) ringPropane-1, 1-dicarboxamide (0.100g,47.7% yield).¹H NMR(400MHz,DMSO-d₆):10.91(s,1H),10.58(s,1H),9.83(s,1H),8.23(d,1H),8.18(d,1H),7.58(m,4H),7.15(m,2H),6.65(dd,1H),2.02(s,3H),1.61(m,2H),1.56(m,2H);MS(ESI)m/z:501.1(M+H⁺)。

Example 3: will be provided withSample A1(0.12g,0.468mmol) was dissolved in dry THF (4.68mL) and triethylamine (0.085mL,0.608mmol) was added. To the direction ofSample B2(0.125g,0.561mmol) was added to the solution and the mixture was stirred at room temperature under argon for 2 hours. The reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated to give a light peach-red oil which was purified by silica gel chromatography (10 to 50% ethyl acetate/hexanes) to give N- (4- (2-chloropyridin-4-yloxy) -2, 5-difluorophenyl) -N' -phenylcyclopropane-1, 1-dicarboxamide (0.164g,79% yield) as a clear solid.¹HNMR(400MHz,DMSO-d₆):11.10(s,1H),9.71(s,1H),8.31(d,1H),8.12(dd,1H),7.60(dd,1H),7.55(m,2H),7.32(t,2H),7.14(d,1H),7.10(m,1H),7.02(dd,1H),1.65(m,2H),1.58(m,2H);MS(ESI)m/z:444.1(M+H⁺)。

N- (4- (2-chloropyridin-4-yloxy) -2, 5-difluorophenyl) -N' -phenylcyclopropane-1, 1-dicarboxamide (0.162g,0.365mmol), acetamide (0.108g,1.825mmol), cesium carbonate (0.178g,0.548mmol) and xanthphos (0.021g,0.036mmol) were combined in dry dioxane (2.61mL) and argon was bubbled through the mixture for 5 minutes. Palladium acetate (6.15mg,0.027mmol) was added and argon bubbled through the mixture for an additional 5 minutes. The reaction flask was connected to a reflux condenser and an argon balloon, and the mixture was heated at 100 ℃ for 20 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and a 4:1 mixture of THF (50mL) and water (50 mL). The aqueous layer was removed and the organic layer was washed with additional water (50mL) and brine (50 mL). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give a light pink film. Dichloromethane (10mL) was added and after a few minutes the solid began to precipitate. Using sonication to precipitate more solidsAnd (3) a body. After standing for 30 minutes, a bright white solid was collected by suction filtration and washed with additional dichloromethane to give N- (4- (2-acetamidopyridin-4-yloxy) -2, 5-difluorophenyl) -N' -phenylcyclopropane-1, 1-dicarboxamide (0.099g,58% yield).¹H NMR(400MHz,DMSO-d₆):10.98(s,1H),10.59(s,1H),9.78(s,1H),8.19(d,1H),8.07(dd,1H),7.65(d,1H),7.55(m,3H),7.32(m,2H),7.09(t,1H),6.71(dd,1H),2.02(s,3H),1.63(m,2H),1.57(m,2H);MS(ESI)m/z:467.2(M+H⁺)。

Example 4: 2-bromoacetamide (1g,7.25mmol) was dissolved in acetonitrile (10.35mL) and dimethylamine in 2M THF (12mL,24.00mmol) was added. The mixture was stirred at room temperature under argon for 48 hours. The reaction mixture was evaporated under reduced pressure and the residue was redissolved in a 1:1 mixture of dichloromethane and methanol (50 mL). It was neutralized within the carbonate resin (2 equivalents) by gentle shaking for 20 hours. The reaction mixture was filtered and the filtrate was evaporated to give 2- (dimethylamino) acetamide (0.740g,100% yield) as a peach-colored solid.¹H NMR(400MHz,DMSO-d₆):7.34(s,1H),7.19(s,1H),3.01(s,2H),2.31(s,6H)。

2- (dimethylamino) acetamide (0.100g,0.974mmol), N- (4- (2-chloropyridin-4-yloxy) -2, 5-difluorophenyl) -N' (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (0.15g,0.325mmol) (as inExample 1Prepared as in (c), cesium carbonate (0.159g,0.487mmol) and xantphos (0.018g,0.032mmol) were combined in dry dioxane (2.5mL) and argon was bubbled through the mixture for 5 minutes. Palladium acetate (5.47mg,0.024mmol) was added and the solution degassed for an additional 5 minutes. The reaction flask was connected to a reflux condenser and an argon balloon and heated at 100 ℃ for 15 hours. The mixture was cooled to room temperature and then washed with ethyl acetate (75mL) and water (45 mL). The aqueous layer was removed and then extracted again with ethyl acetate (25 mL). The combined organic layers were washed with brine (50mL) and dried over magnesium sulfate. The solvent was evaporated to give a pale purple oil which was chromatographed on silica gel (0 to 7% methanol in dichloromethane)This was purified to give N- (4- (2- (2- (dimethylamino) acetamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (0.0823g,48% yield).¹HNMR(400MHz,DMSO-d₆):11.02(s,1H),9.97(s,1H),9.79(s,1H),8.20(d,1H),8.09(dd,1H),7.65(d,1H),7.57(m,3H),7.16(m,2H),6.76(dd,1H),3.06(s,2H),2.25(s,6H),1.63(m,2H),1.57(m,2H);MS(ESI)m/z:528.2(M+H⁺)。

Example 5: sample A3(300mg,1.07mmol) and 1- (4-fluoro-phenylcarbamoyl) -cyclopropanecarboxylic acid (240mg,1.07mmol) (e.g., to DMF (20mL)Sample B1Prepared as in (1) was added HATU (440mg,3.2mmol) and DIEA (280mg,2.1mmol) in portions. The reaction mixture was stirred under nitrogen overnight at 60 ℃. After cooling to room temperature, water (30mL) was added and the solution was extracted using ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine (3 × 50mL), dried over sodium sulfate, and concentrated. The crude product was purified by preparative HPLC to give N- (4- (2-acetamidopyrimidin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (42mg,8% yield) as a white solid.¹H NMR(300MHz,DMSO-d₆):10.95(s,1H),10.40(s,1H),9.75(s,1H),8.49-8.51(d,J=5.7Hz,1H),7.94-8.01(dd,J＝12.3Hz,J＝8.1Hz,1H),7.48-7.60(m,3H),7.05-7.16(m,2H),6.83-6.84(d,J＝5.4Hz,1H),1.92(s,3H),1.53-1.59(d,J=19.2Hz,4H)。

Example 6: n- (4- (2-Chloropyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (0.25g,0.541mmol) (e.g. asExample 1Prepared), cyclopropanecarboxamide (0.092g,1.083mmol), xantphos (0.014g,0.024mmol) and cesium carbonate (0.265g,0.812mmol) were dissolved in dry dioxane (5.41mL) and argon was bubbled through the mixture for 5 minutes. Adding Pd₂(dba)₃(7.44mg,0.00812mmol) and additional argon was bubbled through the system. It was then connected to a reflux condenser and argon balloon and heated at 100 deg.CThe mixture was heated for 20 hours. The reaction mixture was cooled to room temperature and then partitioned between water (40mL) and ethyl acetate (70 mL). The layers were separated and the organic layer was washed with brine (50mL), dried over magnesium sulfate, and evaporated to give a pink solid. It was stirred in dichloromethane (10mL) then the cream solid was collected by suction filtration and washed with additional dichloromethane to give N- (4- (2- (cyclopropanecarboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (0.238g,86% yield).¹HNMR(400MHz,DMSO-d₆) 11.00(s,1H),10.89(s,1H),9.79(s,1H),8.20 (d,1H),8.07(dd,1H),7.63(d,1H),7.56(M,3H),7.16(M,2H),6.74(dd,1H),1.95 (pentapeak, 1H),1.62(M,2H),1.56(M,2H),0.75(M,4H); MS ESI M/z 511.1(M + H) M/z⁺)。

Example 7: n- (4- (2-Chloropyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (200mg,0.43mmol) (as inExample 1Prepared in (e), propionamide (95mg,1.30mmol), xantphos (25mg,0.043mmol) and cesium carbonate (280mg,0.86mmol) were dissolved in dry dioxane (3mL) and argon was then bubbled through the mixture for 10 minutes. Then Pd is added₂(dba)₃(20mg,0.022mmol) and the solution degassed for another 10 minutes. Flask was connected to N₂Balloon and slowly heated to 100 ℃ and stirred overnight. The reaction mixture was cooled to room temperature and diluted with a 4:1 mixture of ethyl acetate and THF (60mL) and water (40 mL). The organic layer was separated and washed with brine, and the aqueous layer was back-extracted with ethyl acetate/THF solution, then extracted with brine. The combined organic layers were dried over sodium sulfate and evaporated, and the residue was purified by silica gel chromatography to give N- (2, 5-difluoro-4- (2-propionamidopyridin-4-yloxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (130mg,60.7% yield).¹H-NMR(400MHz,DMSO-d₆):11.00(s,1H),10.52(s,1H),9.79(s,1H),8.19(d,J=5.6Hz,1H),8.10-8.05(m,1H),7.66(d,J=2.4Hz,1H),7.59-7.53(m,3H),7.16(t,J=8.8Hz,2H),6.74-6.72(m,1H),2.33(q,J＝7.2Hz,2H),1.64-1.55(m,4H),0.99(t,J＝7.2Hz,3H)。

Example 8 (reference Compound E): 1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxylic acid (see example B1, 171mg,0.77mmol), N- (4-methoxybenzyl) -4- (4-amino-3-fluorophenoxy) pyridin-2-amine (see PCT publication No. WO 2008/046003,200mg,0.59mmol), TBTU (284mg,0.88mol) and DIEA (0.12mL,0.73mmol) were combined in DMF (1.5mL) and the resulting mixture was stirred overnight. The reaction mixture was taken up in saturated aqueous NaHCO₃The layers were separated between (20mL) and EtOAc (20 mL). The organic layer was washed with water (10mL), brine (10mL), and 5% aqueous lithium chloride solution (10mL), then MgSO₄Dried and concentrated under vacuum. Methylene chloride was added to the residue, and the resulting slurry was filtered. Using CH₂Cl₂The collected precipitate was washed and then dried under vacuum to give N- (4- (2- (4-methoxybenzylamino) pyridin-4-yloxy) -2-fluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (137mg) as a white solid. The filtrate was concentrated and a second crop was collected (46mg, 57% overall yield). MS (ESI) M/z 545.1(M + H)⁺)。

Will be in CH₂Cl₂A mixture of N- (4- (2- (4-methoxybenzylamino) pyridin-4-yloxy) -2-fluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (160mg,0.29mmol) in (0.2mL) was treated with trifluoroacetic acid (0.4mL,5.26mmol) and the resulting mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness, then the residue was purified by reverse phase silica gel chromatography (25-95% acetonitrile, 0.1% TFA in water). The desired fraction was taken up in saturated aqueous NaHCO₃And EtOAc. Using saturated aqueous NaHCO₃Water and brine, over Na₂SO₄Dried and concentrated in vacuo to give N- (4- (2-aminopyridin-4-yloxy) -2-fluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (52mg,39% yield). MS (ESI) M/z 425.1(M + H)⁺)。

Pyridine (0.058mL,0.72mmol) and acetic anhydride (0.058 mmol) are used13mL,1.4mmol) of the catalyst to treat CH₂Cl₂A solution of N- (4- (2-aminopyridin-4-yloxy) -2-fluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (61mg,0.14mmol) in (3 mL). The resulting mixture was stirred at RT for 2 days. Using saturated aqueous NaHCO₃The reaction was quenched and stirred for a further 2 h. The mixture was diluted with EtOAc (30mL) and then saturated aqueous NaHCO was used₃(20mL), water (20mL) and brine (20 mL). The mixture was concentrated in vacuo and then purified by silica gel chromatography to give N- (4- (2-acetamidopyridin-4-yloxy) -2-fluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (46mg,69% yield).¹H NMR(400MHz,DMSO DMSO-d₆):10.56(s,1H),10.54(s,1H),9.96(s,1H),8.18(d,J=5.8Hz,1H),7.92(t,1H),7.65(d,J=1.9Hz,1H),7.59(m,2H),7.24(dd,J=11.2,2.5Hz,1H),7.15(m,2H),7.01(m,1H),6.68(dd,J=5.7,2.3Hz,1H),2.02(s,3H),1.60-1.52(m,4H);MS(ESI)m/z:467.2(M+H⁺)。

Example 9: n- (4- (2-chloropyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) propane-1, 1-dicarboxamide (3g,6.5mmol) (as prepared in example 1), tert-butyl carbamate (2.3g,19.5mmol), Xantphos (0.37g,0.65mmol) and cesium carbonate (4.2g,13mmol) were dissolved in dry dioxane (50mL) and argon was bubbled through the mixture for 10 minutes. Then Pd is added₂(dba)₃(0.3g,0.33mmol) and bubbling with argon for another 10 minutes. The flask was connected to a reflux condenser and argon balloon, slowly heated to 100 ℃, and stirred overnight. The reaction mixture was cooled to RT. It was diluted with ethyl acetate (100mL) and water (80 mL). The organic layer was separated and washed with brine. The aqueous layer was back-extracted with ethyl acetate and then washed with brine. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give tert-butyl 4- (2, 5-difluoro-4- (1- (4-fluorophenylcarbamoyl) cyclopropanecarboxamido) phenoxy) pyridin-2-ylcarbamate (1.8g,51% yield).¹H NMR(400MHZ,DMSO-d₆):11.03(s,1 H),9.88(s,1H),9.78(s,1H),8.13-8.05(m,2H),7.59-7.53(m,3H),7.33(d,J＝2.4Hz,1H),7.18-7.13(m,2H),6.63(d,J＝2.4Hz,1H),1.63-1.62(m,2H),1.58-1.56(m,2H),1.40(s,9H)。

To CH₂Cl₂A solution of tert-butyl 4- (2, 5-difluoro-4- (1- (4-fluorophenylcarbamoyl) cyclopropanecarboxamido) phenoxy) pyridin-2-ylcarbamate (1.8g,3.3mmol) in (100mL) was added to TFA (5mL), and the mixture was stirred at room temperature overnight. With saturated NaHCO₃The solution adjusts the reaction mixture to pH>7 washing the separated organic layer with brine over Na₂SO₄Dried and concentrated under reduced pressure to give N- (4- ((2-aminopyridin-4-yl) oxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (1.2g, 82% yield).¹H-NMR(400MHz,DMSO-d₆):10.99(s,1H),9.76(s,1H),8.04(dd,J＝12.4,7.6Hz,1H),7.79(d,J=6.0Hz,1H),7.58-7.55(m,2H),7.47(dd,J＝10.8,7.2Hz,1H),7.16(t,J＝8.8Hz,2H),6.16(dd,J=6.0,2.4Hz,1H),6.00(br s,2H),5.81(d,J＝2.0Hz,1H),1.65-1.62(m,2H),1.56-1.53(m,2H);MS(ESI):m/z 443.1[M+H]⁺。

To a solution of N- (4- ((2-aminopyridin-4-yl) oxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (130mg,0.29mmol) in 10mL of anhydrous tetrahydrofuran was added diisopropylethylamine (75mg,0.58 mmol). A solution of methoxyacetyl chloride (34.5mg,0.32mmol) in THF (1mL) was added dropwise at 0 deg.C. The resulting reaction mixture was stirred at r.t. for 0.5 h. It was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative-TLC to give N- (2, 5-difluoro-4- ((2- (2-methoxyacetamido) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (75mg,50% yield).¹H NMR(400MHz,CDCl₃):9.79(s,1H),8.89(s,1H),8.53(s,1H),8.30(dd,J=12.0,7.2Hz,1H),8.17(d,J=5.6Hz,1H),7.83(d,J=2.4Hz,1H),7.49-7.45(m,2H),7.07-6.99(m,3H),6.64(dd,J=5.6,2.4Hz 1H),3.98(s,2H),3.49(s,3H),1.78-1.66(m,4H);MS(ESI):m/z 515.2[M+H]⁺。

Example 10: n- (4- (2-chloropyridin-4-yloxy) -2, 5-difluorophenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (250mg,0541mmol) (prepared as in example 1), cesium carbonate (353mg,1.083mmol), isobutyramide (236mg,2.71mmol), and xantphos (31mg,54 μmol) were placed in degassed dioxane (5 mL). To this solution was added tris (dibenzylideneacetone) dipalladium (0) (25mg, 27. mu. mol). The mixture was warmed to 100 ℃ overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (30mL), and filtered to remove solids. Using aqueous NaHCO₃The filtrate was washed (30mL) and brine (30 mL). Passing the organic phase over Na₂SO₄Dried and evaporated under reduced pressure to give a foam. The foam was purified by reverse phase silica gel chromatography (35-80% acetonitrile/water/0.1% TFA). The fractions containing the product were combined and evaporated under reduced pressure. Using saturated aqueous NaHCO₃The resulting aqueous mixture was treated (4mL) and allowed to stand. The solid was collected by filtration, washed with water (2x5mL), and dried over night at 80 ℃ via a high vacuum line to give N- (2, 5-difluoro-4- (2-isobutyramidopyridin-4-yloxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (116mg,41% yield).¹HNMR(400MHz,DMSO-d₆)11.00(s,1H),10.53(s,1H),9.78(s,1H),8.19(d,1H),8.06-8.10(m,1H),7.66(s,1H),7.60-7.53(m,3H),7.15(t,2H),6.75-6.73(m,1H),2.68(m,1H),1.62-1.51(m,4H),1.00(d,6H);MS(ES-API)m/z:513.2(M+H⁺)。

Example 11: n- (4- ((2-Aminopyridin-4-yl) oxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (150mg,0.34mmol) in DMF (2mL) (as atExample 9Prepared as in (c) and 2-cyanoacetic acid (44mg,0.51mmol) were added HATU (258mg,0.68mmol) and DIEA (130mg,1mmol), and the mixture was stirred under nitrogen at 60 ℃ overnight. The reaction mixture was cooled to room temperature using ethyl acetate (50mL) and H₂O (50mL) and the organic layer was washed with brine, dried and concentrated under reduced pressureAnd (4) shrinking. The residue was purified by preparative-TLC to give N- (4- (2- (2-cyanoacetamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (70mg, 64.5% yield).¹H-NMR(400MHz,DMSO-d₆):10.99(s,1H),10.94(s,1H),9.81(s,1H),8.23(d,J=5.6Hz,1H),8.08(dd,J=12.4,6.8Hz,1H),7.59-7.55(m,4H),7.15(t,J=8.8Hz,2H),6.80(dd,J=6.0,2.4Hz,1H),3.92(s,2H),1.61-1.56(m,4H);MS(ESI):m/z510.2[M+H]⁺。

Example 12: n- (4- ((2-aminopyridin-4-yl) oxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide in DMF (5mL)(440mg,1mmol)(as inExample 9Prepared as in (c) and 1- (tert-butoxycarbonyl) azetidine-3-carboxylic acid (402mg,2mmol) was added to HATU (1.1g,3mmol) followed by DIEA (516mg,4 mmol). The mixture was bubbled with nitrogen and then stirred at 50 ℃ overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give tert-butyl 3- (4- (2, 5-difluoro-4- (1- (4-fluorophenylcarbamoyl) cyclopropanecarboxamido) phenoxy) pyridin-2-ylcarbamoyl) azetidine-1-carboxylate (250mg,40% yield).¹H-NMR(400MHz,DMSO-d₆):11.01(s,1H),10.72(s,1H),9.79(s,1H),8.19(d,J=5.6Hz,1H),8.10-8.05(m,1H),7.66(s,1H),7.58-7.53(m,3H),7.14(t,J＝8.8Hz,2H),6.77-6.75(m,1H),3.90-3.84(m,4H),3.55-5.53(m,1H),1.63-1.53(m,4H),1.33(s,9H)。

To CH at 0 DEG C₂Cl₂A solution of tert-butyl 3- (4- (2, 5-difluoro-4- (1- (4-fluorophenylcarbamoyl) cyclopropanecarboxamido) phenoxy) pyridin-2-ylcarbamoyl) azetidine-1-carboxylate (220mg,0.35mmol) in (4mL) was added to TFA (0.2mL), and the mixture was stirred at room temperature overnight. Saturated NaHCO was added dropwise₃Solution to pH>7 and use of CH₂Cl₂(2x50mL) to extract the mixture. The combined organic layers were washed with brine, over Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by HPLC separation to give N- (4- (2- (azetidine-3-carboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (16mg, yield 8.7%).¹H-NMR(400MHz,MeOH-d₄):9.50(s),8.46(d,J=7.2Hz,1H),8.33(dd,J=7.2Hz,12.4Hz,1H),7.53-7.43(m,3H),7.26(dd,J＝7.2Hz,2.4Hz,1H),7.10(t,J=8.4Hz,2H),6.75(d,J=2.4Hz,1H),4.61-4.54(m,1H),3.63-3.58(m,1H),3.49-3.44(m,1H),3.31-3.29(m,1H),3.27-3.25(m,1H),1.75-1.73(m,4H);MS(ESI):m/z 443.2[M+H]⁺。

Example 13: to a solution of N- (4- (2-chloropyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (200mg,0.45mmol) (as prepared in example 9) and cyclobutanecarboxylic acid (90mg,0.9mmol) in DMF (3mL) was added HATU (513mg,1.35mmol) followed by DIEA (516mg,4 mmol). The mixture was sparged with nitrogen and stirred at 60 ℃ overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N- (4- (2- (cyclobutanecarboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (97mg, yield 41.1%).¹H NMR(400MHz,DMSO-d₆):11.02(s,1H),10.42(s,1H),9.80(s,1H),8.18(d,J=6.0Hz,1H),8.08(dd,J=12.4,6.8Hz,1H),7.68(s,1H),7.60-7.54(m,3H),7.17(t,J=8.8Hz,2H),6.73(dd,J=5.6,2.4Hz,1H),2.18-2.02(m,4H),1.92-1.83(m,1H),1.76-7.69(m,1H),1.62-1.55(m,4H);MS(ESI):m/z 525.1[M+H]。

Example 14: to anhydrous CH₂Cl₂A solution of (R) -2-methoxy-propionic acid (300mg,2.88mmol) and N-methylmorpholine (432mg,4.32mmol) in (D) was added dropwise to isobutyl chloroformate (588mg, 4.32 mmol). The resulting mixture was stirred at RT for 1 h. Adding N- (4- (2-chloropyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-diformylAmine (200mg,0.452mmol) and the resulting mixture was then stirred at RT for 12 h. The reaction mixture was concentrated in vacuo and then purified by HPLC separation to give (R) -N- (2, 5-difluoro-4- ((2- (2-methoxypropionylamino) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (50mg, 21%).¹H NMR(400MHz,CDCl₃):9.79(s,1H),9.07(s,1H),8.51(s,1H),8.32-8.27(m,1H),8.16(d,J=5.6Hz,1H),7.83(d,J=2Hz,1H),7.48-7.44(m,2H),7.06-6.98(m,3H),6.66-6.64(m,1H),3.82(q,J=6.8Hz,1H),3.50(s,3H),1.75-1.67(m.4H),1.42(d,J=6.8Hz,3H);MS(ESI):m/z 529.1[M+H]⁺。

Example 15: to anhydrous CH₂Cl₂A solution of (R) -2-benzyloxypropionic acid (500mg,2.78mmol) and N-methylmorpholine (416mg,4.16mmol) in (D) was added dropwise to isobutyl chloroformate (566mg,4.32 mmol). The mixture was stirred at 25 ℃ for 1 h. N- (4- ((2-aminopyridin-4-yl) oxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (200mg,0.452mmol) was added and the resulting mixture was stirred at 25 ℃ for 12 h. The reaction mixture was concentrated in vacuo to give (R) -N- (4- ((2- (2- (phenylmethyloxy) propionamido) pyridin-4-yl) oxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (200mg, 71.5%). It was used without further purification.

To a solution of (R) -N- (4- ((2- (2- (phenylmethyloxy) propionamido) pyridin-4-yl) oxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (200mg,0.331mmol) in methanol (20mL) was added Pd (OH)₂(50 mg). The mixture was then hydrogenated (1atm) for 12 h. The reaction mixture was filtered, concentrated, and purified by HPLC chromatography to give (R) -N- (2, 5-difluoro-4- ((2- (2-hydroxypropionamido) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (20mg,11.7% yield).¹H NMR(400MHz,CD₃OD):8.23-8.18(m,2H),7.69(s,1H),7.54-7.50(m,2H),7.31-7.28(m,1H),7.09-7.05(m,2H),6.86-6.84(m,1H),4.28-4.23(q,J=6.8Hz,1H),1.76-1.67(m,4H),1.39(d,J=6.8Hz,3H);MS(ESI);m/z 515.1[M+H]⁺。

Example 16: n- (4- (2-chloropyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (160mg,0.34mmol) (prepared as in example 1), 2-dimethyl-propionamide (100mg,1mmol), xantphos (40mg,0.068mmol) and cesium carbonate (222mg,0.68mmol) were dissolved in dry dioxane (2mL) and argon was bubbled through the mixture for 10 minutes. Then Pd (OAc) is added₂(8mg,0.034mmol) and the solution degassed for another 10 minutes. The mixture was heated to 100 ℃ and stirred overnight. The reaction mixture was cooled to RT and diluted with EtOAc (20mL) and water (15 mL). The organic layer was separated and washed with brine. The aqueous layer was extracted with EtOAc, and the extract was washed with brine. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative-TLC to give N- (2, 5-difluoro-4- ((2-pivaloylamidopyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (72mg,40% yield).¹H-NMR(400MHz,DMSO-d₆):8.19-8.17(m,2H),7.69(s,1H),7.53-7.51(m,2H),7.24(br t,J=7.2Hz,1H),7.10-7.05(m,2H),6.73(brs,1H),1.73-1.69(m,4H),1.27(s,9H);MS(ESI);m/z 527.3[M+H]⁺。

Example 17: to anhydrous CH₂Cl₂A solution of (S) -2-methoxy-propionic acid (400mg,3.84mmol) and N-methylmorpholine (577mg,5.77mmol) in (I) was added dropwise to isobutyl chloroformate (773mg,5.77mmol) and the resulting mixture was stirred at 25 ℃ for 1 h. N- (4- ((2-aminopyridin-4-yl) oxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (200mg,0.452mmol) was added to the mixture. The resulting mixture was stirred at 25 ℃ for 12 h. The reaction mixture was concentrated under reduced pressure and purified by HPLC chromatography to give (S) -N- (2, 5-difluoro-4- ((2- (2-methoxypropionylamino) pyridin-4-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (50mg,21% yield).¹HNMR (400MHz, methanol-d)₄) 8.21-8.16(m,2H),7.65(d, J =2.4Hz,1H),7.55-7.51(m,2H),7.26(dd, J =10.4,6.8Hz,1H),7.10-7.05(m,2H),6.76(q, J =5.6,2.4Hz,1H),3.90(q, J =6.8Hz,1H),3.44, (s,3H),1.74-1.69(m,4H),1.38(d, J =6.8Hz,3H) [ lack of 3NH 3];MS(ESI):m/z 528.9[M+H]⁺。

Example 18: to anhydrous CH₂Cl₂A solution of (S) -2-acetoxy-propionic acid (300mg,2.278mmol) and N-methylmorpholine (341mg,3.41mmol) in (D) was added dropwise to isobutyl chloroformate (457mg,3.41 mmol). The resulting mixture was stirred at 25 ℃ for 1 h. N- (4- ((2-aminopyridin-4-yl) oxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (250mg,0.578mmol) was added and the resulting mixture was stirred at 25 ℃ for 12 h. The reaction mixture was concentrated under reduced pressure to give (S) -1- ((4- (2, 5-difluoro-4- (1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxamido) phenoxy) pyridin-2-yl) amino) -1-oxopropan-2-yl acetate (180mg,55.9% yield) without further purification.

To MeOH-H₂A solution of (S) -1- ((4- (2, 5-difluoro-4- (1- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxamido) phenoxy) pyridin-2-yl) amino) -1-oxopropan-2-yl acetate (180mg,0.323mmol) in a solution of O (3:1,20mL) was added potassium carbonate (111.6mg,0.809mmol) and the mixture was stirred at 25 ℃ for 12 h. The reaction mixture was concentrated and then purified by preparative-TLC to give (S) -N- (2, 5-difluoro-4- ((2- (2-hydroxypropionamido) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (100mg,60% yield).¹H NMR (400MHz, methanol-d)₄):8.21-8.16(m.2H),7.78(d,J=2.4Hz,1H),7.54-7.51(m,2H),7.28-7.24(m,1H),7.10-7.05(m,2H),6.76-6.74(dd,J=6.0,2.4Hz,1H),4.23(q,J=6.8Hz,1H),1.75-1.67(m,4H),1.39(d,J=6.8Hz,3H);MS(ESI):m/z 515.2[M+H] ⁺。

Example 19: in N₂Down in anhydrous CH₂Cl₂N- (4-, (30mL) inA solution of (2-aminopyridin-4-yl) oxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (250mg,0.565mmol) and 2-fluoro-2-methylpropionic acid (108mg,1.02mmol) was added to HATU (323mg,0.85mmol) and DIPEA (2.5 mL). The reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The residue was poured into water (100mL), extracted with ethyl acetate (3 × 50mL), washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give N- (2, 5-difluoro-4- ((2- (2-fluoro-2-methylpropionamido) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (128mg,43% yield).¹H-NMR (400MHz, methanol-d)₄):8.21-8.17(m,2H),7.73(d,J＝2.4Hz,1H),7.54-7.51(m,2H),7.23(dd,J＝10.8,7.2Hz,1H),7.08-7.04(m,2H),6.75(dd,J＝5.6,2.4Hz,1 H),1.76-1.69(m,4H),1.62(s,3H),1.56(s,3H);MS(ESI):m/z 531.1[M+H] ⁺。

Biological data

c-MET kinase assay

The activity of c-MET kinase (seq. ID No.2) was determined by preparing ADP by a kinase reaction coupled to the pyruvate kinase/lactate dehydrogenase system (e.g., Schinder et al Science2000,289, pp 1938-. In this assay, the oxidation of NADH (and thus the decrease at A340 nm) is monitored spectrophotometrically continuously. The reaction mixture (100. mu.l) contained c-MET (c-MET residue: 956-1390 from Invitrogen, cat # PV3143,6nM), polyE4Y (1mg/mL), MgCl₂(10mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenolpyruvate (1mM), and 90mM NADH (0.28mM) in Tris buffer containing 0.25mM DTT, 0.2% octyl glucoside, and 1% DMSO, pH 7.5. Test compounds were incubated with c-MET (seq. id No.2) and other reagents for 0.5h at 22 ℃ before ATP (100 μ M) was added to start the reaction. The absorption at 340nm was monitored continuously at 30 ℃ for 2 hours on a Polarstar Optima microplate reader (BMG). The reaction rate was calculated using a time range of 1.0 to 2.0 h. Percent inhibition was obtained by comparing the reaction rate to that of a control (i.e., no test compound). Using as in GThe software program embodied in the rapphPad Prism software package calculated the IC from a series of percent inhibition values determined at a series of inhibitory concentrations₅₀The value is obtained.

c-MET kinase (Seq ID No 2)

MSYYIHHHHHIDYDIPTTENLYFQGAMLVPRGSPWIPFTMKKRKQIKDLGSELVRYDARV

HTPHLDRLVSARSVSPTTEMVSNESVDYRATFPEDQFPNSSQNGSCRQVQYPLTDMSPILTS

GDSDISSPLLQNTVHIDLSALNPELVQAVQHVVIGPSSLIVHFNEVIGRGHFGCVYHGTLLD

NDGKKIHCAVKSLNRITDIGEVSQFLTEGHMKDFSHPNVLSLLGICLRSEGSPLVVLPYMKH

GDLRNFIRNETHNPTVKDLIGFGLQVAKGMKYLASKKFVHRDLAARNCMLDEKFTVKVA

DFGLARDMYDKEYYSVHNKTGAKLPVKWMALESLQTQKFTTKSDVWSFGVLLWELMTR

GAPPYPDVNTFDITVYLLQGRRLLQPEYCPDPLYEVMLKCWHPKAEMRPSFSELVSRISAIF

STFIGEHYVHVNATYVNVKCVAPYPSLLSSEDNADDEVDTRPASFWETS

c-KIT kinase assay

The activity of c-KIT kinase (seq. ID No.1) was determined by preparing ADP by a kinase reaction coupled to the pyruvate kinase/lactate dehydrogenase system (e.g., Schinder et al Science2000,289, pp 1938-1942). In this assay, the oxidation of NADH (and thus the decrease at A340 nm) is monitored spectrophotometrically continuously. The reaction mixture (100. mu.l) contained c-KIT (c-KIT residue T544-V976 from ProQinase,5.4nM), polyE4Y (1mg/mL), MgCl₂(10mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenolpyruvate (1mM), and 90mM NADH (0.28mM) in Tris buffer containing 0.2% octyl glucoside and 1% DMSO, pH 7.5. Test compounds were incubated with c-KIT (seq. ID No.1) and other reagents for less than 2min at 22 ℃ before ATP (200. mu.M) was added to start the reaction. At 30 ℃ in Polarstar OThe absorbance at 340nm was monitored continuously on a ptima plate reader (BMG) for 0.5 hour. The reaction rate was calculated using a time range of 0 to 0.5 h. Percent inhibition was obtained by comparing the reaction rate to that of a control (i.e., no test compound). IC was calculated from a series of percent inhibition values determined at a series of inhibitory concentrations using a software program as implemented in the GraphPad Prism software package₅₀The value is obtained.

c-KIT with N-terminal GST fusion (Seq ID No.1)

LGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVK

LTQSMAHRYIADKHNMLGGCPKERAEISMLEGAVDIRYGVSRIAYSKDFETLKVDFLSKLP

EMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAI

PQIDKYLKSSKYIWPLQGWQATFGGGDHPPKSDLVPRHNQTSLYKKAGSAAAVLEENLYF

QGTYKYLQKPMYEVQWKVVEELNGNNYVYIDPTQLPYDHKWEFPRNRLSFGKTLGAGAF

GKVVEATAYGLIKSDAAMTVAVKMLKPSAHLTEREALMSELKVLSYLGNHMNIVNLLGA

CTIGGPTLVITEYCCYGDLLNFLRRKRDSFICSKQEDHAEAALYKNLLHSKESSCSDSTNEY

MDMKPGVSYVVPTKADKRRSVRIGSYIERDVTPAIMEDDELALDLEDLLSFSYQVAKGMA

FLASKNCIHRDLAARNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWMAPESIF

NCVYTFESDVWSYGIFLWELFSLGSSPYPGMPVDSKFYKMIKEGFRMLSPEHAPAEMYDI

MKTCWDADPLKRPTFKQIVQLIEKQISESTNHIYSNLANCSPNRQKPVVDHSVRINSVGST

ASSSQPLLVHDDV

KDR kinase assay

Determination of K1

The activity of KDR kinase is determined by preparing ADP by a kinase reaction coupled to the pyruvate kinase/lactate dehydrogenase system (e.g., Schinder et al, science2000,289, pp. 1938-1942). In this assay, the oxidation of NADH (and thus the decrease at A340 nm) is monitored spectrophotometrically continuously. The reaction mixture (100. mu.l) contains KDR: (Seq ID No.31.5nM to 7.1nM, nominal concentration), polyE4Y (1mg/mL), pyruvate kinase (3.5 units), lactate dehydrogenase (5.5 units), phosphoenolpyruvate (1mM), and a composition comprising 0.13% octyl glucoside, 13mM MgCl₂NADH (0.28mM) in 60mM Tris buffer, 6.8mM DTT and 3.5% DMSO, pH 7.5. The reaction was started by adding ATP (0.2mM, final concentration). The absorption at 340nm is monitored continuously at 30 ℃ for 3h on a Polarstar Optima microplate reader (BMG) or a similarly functioning instrument. The reaction rate was calculated using a time range of 1h to 2 h. Percent inhibition was obtained by comparing the reaction rate to that of a control (i.e., no test compound). IC was calculated from a series of percent inhibition values determined at a series of inhibitory concentrations using a software program as implemented in the GraphPad Prism software package₅₀The value is obtained.

Determination of K2

KDR kinase assay K2 was the same as assay K1 except: (1) enzyme was used at a nominal concentration of 2.1 nM; (2) the reaction was preincubated at 30 ℃ for 2h before starting with ATP; and (3) start the reaction using 1.0mM ATP (final concentration).

Determination of K3

KDR kinase assay K3 was the same as assay K1 except: (1) enzyme was used at a nominal concentration of 1.1 nM; (2) the buffer components per 100. mu.l of reaction mixture were as follows: contains 0.066% octyl glucoside, 17mM MgCl at pH7.5₂And 1% DMSO in 75mM Tris buffer; (3) the final concentration of DTT was 0.66 mM; (4) the reaction was preincubated for 1h at 30 ℃ before starting with ATP; and (5) start the reaction using 1.0mM ATP (final concentration).

KDR protein sequence for screening (seq. ID No.3)

DPDELPLDEHCERLPYDASKWEFPRDRLKLGKPLGRGAFGQVIEADAFGIDKTATCRTVAVKML

KEGATHSEHRALMSELKILIHIGHHLNVVNLLGACTKPGGPLMVIVEFCKFGNLSTYLRSKRNEF

VPYKVAPEDLYKDFLTLEHLICYSFQVAKGMEFLASRKCIHRDLAARNILLEKNVVKICDFGLA

RDIYKDPDYVRKGDARLPLKWMAPETIFDRVYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEF

CRRLKEGTRMRAPDYTTPEMYQTMLDCWHGEPSQRPTFSELVEHLGNLLQANAQQD

FMS kinase assay

The FMS kinase activity is determined by preparing ADP via a kinase reaction coupled to a pyruvate kinase/lactate dehydrogenase system (e.g., Schinder et al Science2000,289, pp 1938-1942). In this assay, the oxidation of NADH (and thus the decrease at A340 nm) is monitored spectrophotometrically continuously. The reaction mixture (100. mu.l) contained FMS (purchased from Invitrogen or Millipore,6nM), polyE4Y (1mg/mL), MgCl₂(10mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenolpyruvate (1mM), and NADH (0.28mM) and ATP (500. mu.M) in 90mM Tris buffer containing 0.2% octyl glucoside and 1% DMSO, pH 7.5. Inhibition of the reaction was initiated by mixing serial dilutions of the test compound with the above reaction mixture. The absorbance at 340nm was monitored continuously at 30 ℃ for 4 hours on a Polarstar Optima or Synergy2 microplate reader. The reaction rate was calculated using a time range of 2 to 3 h. Percent inhibition was obtained by comparing the reaction rate to that of a control (i.e., no test compound). IC was calculated from a series of percent inhibition values determined at a series of inhibitory concentrations using a software program as implemented in the GraphPad Prism software package₅₀The value is obtained.

EBC-1 cell culture

EBC-1 cells (catalog number JCRB0820) were obtained from the resource library of the Japanese Health Science research (Japan Health Science research resources Bank) Osaka, Japan. Brief description of the drawingsThe cells were grown at 37 ℃ with 5% CO₂95% humidity in DMEM supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA). Cells were allowed to expand until 70-95% confluence was reached, at which time they were sub-cultured or harvested for assay.

EBC-1 cell proliferation assay

Serial dilutions of the test compounds were dispensed into 96-well black transparent plates (Corning, NY). For each cell line, five thousand cells per well were added in 200 μ L of intact growth medium. The plates were incubated at 37 ℃ with 5% CO₂Incubate at 95% humidity for 67 hours. At the end of the incubation period, 40 μ l of 440 μ M resazurin in PBS (Sigma, St. Louis, Mo.) solution was added to each well and additionally at 37 ℃ with 5% CO₂Incubate 5 hours at 95% humidity. Plates were read on a Synergy2 plate reader (Biotek, Winooski, VT) using 540nM excitation and 600nM emission. Data were analyzed using Prism software (GraphPad, San Diego, Calif.) to calculate IC₅₀The value is obtained.

MKN-45 cell culture

MKN-45 cells (catalog number JCRB0254) were obtained from the Japanese health science research resource pool of Osaka, Japan. Briefly, cells were grown at 37 ℃ with 5% CO₂RPMI 1640 medium supplemented with 10% characterised fetal bovine serum at 95% humidity (Invitrogen, Carlsbad, CA). Cells were allowed to expand until 70-95% confluence was reached, at which time they were sub-cultured or harvested for assay.

MKN-45 cell proliferation assay

Serial dilutions of the test compounds were dispensed into 96-well black transparent plates (Corning, NY). Five thousand cells were added per well in 200 μ L of complete growth medium. The plates were incubated at 37 ℃ with 5% CO₂Incubate at 95% humidity for 67 hours. At the end of the incubation period, 40 μ l of 440 μ M resazurin (Sigma, St. Louis, Mo.) solution in PBS was added to each well and 5% CO at 37 ℃ additionally₂Incubate for 5h at 95% humidity. Using 540nM excitation and 600nM emission at SPlates were read on a ynergy2 plate reader (Biotek, Winooski, VT). Data were analyzed using Prism software (GraphPad, San Diego, Calif.) to calculate IC₅₀The value is obtained.

RON kinase assay

The activity of RON kinase is determined by a radioactive filtration binding assay, wherein the assay³³Of P-gamma-ATP to a substrate³³And P is combined. In the case of this measurement, the measurement,³³the indicator of P detection is RON phosphorylation activity, which is directly proportional to the amount of phosphorylated peptide substrate (KKSRGDYMTMQIG). Initially, the reaction mixture comprises: 400nM RON, 20mM HEPES (pH7.5), 10mM MgCl₂、2mM MnCl₂、1mM EGTA、0.02%Brij 35、0.02mg/mLBSA、0.1mM Na₃VO₄And 2mM DTT. The reaction mixture was incubated with the compound for 30 minutes at room temperature. To start the reaction, an equal amount of 20. mu.M ATP and 0.4mg/mL peptide substrate was added, followed by incubation at room temperature for 2 hours. The final assay conditions were: 200nM RON, 10. mu.M ATP, 0.2mg/mL substrate, 20mM HEPES (pH7.5), 10mM MgCl₂、1mM EGTA、0.02%Brij 35、0.02mg/mL BSA、0.1mM Na₃VO₄2mM DTT and 1% DMSO. IC was calculated from a range of% activity values determined at a range of inhibitory concentrations using a software program as implemented in GraphPad Prism software package₅₀The value is obtained.

RON sequence/protein information (UniProtKB/Swiss-Prot entry Q04912)

GST-tagged recombinant human RON, amino acids 983-1400. Expressed in insect cells.

FLT1 kinase assay

Determining the activity of FLT1 kinase by a radiofiltration binding assay, wherein the determination³³Of P-gamma-ATP to a substrate³³And P is combined. In the case of this measurement, the measurement,³³the index of P detection is FLT1 phosphorylation activity, which is combined with phosphorylation peptide substrate poly [ Glu: Tyr]The amount of (4:1) is directly proportional. Initially, the reaction mixture comprises: 400nM FLT1, 20mM HEPES (M)pH 7.5)、10mM MgCl₂、2mM MnCl₂、1mM EGTA、0.02%Brij 35、0.02mg/mL BSA、0.1mM Na₃VO₄And 2mM DTT. The reaction mixture was incubated with the compound for 30 minutes at room temperature. To start the reaction, an equal amount of 20. mu.M ATP and 0.2mg/mL peptide substrate was added, followed by incubation at room temperature for 2 hours. The final assay conditions were: 200nM FLT1, 10. mu.M ATP, 0.1mg/mL substrate, 20mM HEPES (pH7.5), 10mM MgCl₂、1mM EGTA、0.02%Brij 35、0.02mg/mL BSA、0.1mMNa₃VO₄2mM DTT and 1% DMSO. IC was calculated from a range of% activity values determined at a range of inhibitory concentrations using a software program as implemented in GraphPad Prism software package₅₀The value is obtained.

FLT1 sequence/protein information (UniProtKB/Swiss-Prot entry P17948)

GST-tagged recombinant human FLT1, amino acids 781-1338. Expressed in insect cells.

RET kinase assay

The activity of RET kinases is determined by preparing ADP by a kinase reaction coupled to a pyruvate kinase/lactate dehydrogenase system (e.g., Schinder et al Science2000,289, pp 1938-1942). In this assay, the oxidation of NADH (and thus the decrease at A340 nm) is monitored spectrophotometrically continuously. The reaction mixture (100. mu.l) contained RET (amino acid residues 658-1114 from Invitrogen, 2nM), polyE4Y (1.5mg/mL), MgCl₂(18mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenolpyruvate (1mM), and NADH (0.28mM) in 90mM Tris buffer, pH7.5, containing 0.2% octyl glucoside, 1mM DTT, and 1% DMSO. Test compounds were incubated with RET kinase and other reactive reagents at 22 ℃ before ATP (500. mu.M) was added to start the reaction<And 2 min. The absorbance at 340nm was monitored continuously at 30 ℃ for 3 hours on a BioTek Synergy2 microplate reader. The reaction rate was calculated using a time range of 1 to 2 h. Percent inhibition was obtained by comparing the reaction rate to that of a control (i.e., no test compound). Using software as implemented in the GraphPadprism software packageProgram calculates IC from a series of percent inhibition values determined at a series of inhibitory concentrations₅₀The value is obtained.

RET sequence/protein information (UniProtKB/Swiss-Prot entry P07949)

GST-tagged recombinant human RET, amino acids 658-1114. Expressed in insect cells.

The compounds of formula I exhibit inhibitory activity in one or more of the foregoing assays when evaluated at a concentration of ≦ 10. mu.M.

When the central phenyl ring of the compounds disclosed herein comprises different para-disubstituted patterns, an unexpected increase in potency and/or selectivity is observed. Furthermore, it is speculated that the presence of certain R3 moieties on the heteroaromatic ring containing a monocyclic nitrogen, together with the para-disubstituted pattern of the central benzene ring, serves to unexpectedly produce further improvements in potency and/or selectivity. It is speculated that the identity and position of the central portion on the heteroaromatic ring with respect to the ether oxygen linkage and the ring nitrogen atom contribute to these results. For example, in the compounds described herein, the NH-R3 moiety is located sterically in the meta position relative to the ether oxygen linkage and in the ortho position relative to the ring nitrogen atom.

The potency and selectivity of the unexpected compounds characterized by formula I are exemplified in the data shown in table 1. Compound F, compound G and compound H are disclosed in U.S. patent publication No. 2008/0319188a1 (hereinafter the "' 188 application"). Data for compound F, compound G, and compound H were selected from the values disclosed in the '188 application (pages 96-97) and in U.S. patent publication No. 2009/0227556a1 (hereinafter the "' 556 application"). Data for compound D (example 1) and compound E (example 8) were obtained by the methods described in the biological data section, as shown below.

TABLE 1

The structures of compound F, compound G, compound H, compound D, and compound E are as follows:

compound D (example 1)

Reference Compound E (example 8)

Reference compound F

Reference Compound G

Reference Compound H

Cyclopropane diamide compound F, compound G and compound H are disclosed in examples 15, 92 and 91, respectively, of the' 188 application. As shown in table 1, compound F and compound G were recorded to inhibit MET kinase bioactivity with comparable IC50 values of 53nM and 47nM, respectively.

The structures of compound F and compound G are nearly identical, except that compound F is monofluorinated in the central phenyl ring, while compound G is difluorinated, with the two fluorines being para-oriented with respect to each other in the central phenyl ring.

In contrast, it was unexpectedly found that compound D disclosed herein potently inhibits c-MET kinase with an IC of 4nM₅₀The value is obtained. Compound D was 6.5 times more potent on c-MET kinase than its monofluoro analogue compound E (4nM vs 26 nM; see Table 1). This 6.5-fold higher potency for MET kinase was unexpected in view of the c-MET inhibition data for compound G compared to its corresponding monofluoro analog compound F. As reported in the' 188 application, compound G and compound F showed substantially equivalent potency to c-MET kinase (53 nM vs 47 nM; 1.1-fold ratio of potency, respectively). See the' 188 application, pages 96-97. Compound H was also reported to be a potent MET kinase inhibitor with an IC50 of 4 nM. As above, compound H is difluorinated similarly to compound D, having two fluorines on the central phenyl ring that are para-oriented with respect to each other. However, compound H did not exhibit the selectivity for c-MET inhibition observed in compound D.

It was also surprisingly found that compound D showed a very high kinase selectivity for RON, RET, VEGFR-1 and VEGFR-2 kinases compared to compound E. See table 1. RON is a kinase closely related to the MET kinase subfamily, and inhibitors of MET kinase are generally not selective for RON. However, compound D was >1,250-fold selective for RON kinase over MET kinase, and compound E was only 3.85-fold selective for RON kinase over MET kinase. See table 1. Furthermore, compound D was > 825-fold selective for RET kinase over MET kinase, but compound E was only 1.65-fold selective for RET kinase. Furthermore, compound D was 19.75 times more selective for VEGFR-1 kinase than MET kinase, but compound E was significantly less selective for VEGFR-1 kinase: 6.15 times of MET kinase. Finally, compound D was 13-fold more selective for VEGFR-2 kinase than MET kinase, but compound E was significantly less selective for VEGFR-2 kinase: 4.69 times of MET kinase.

In contrast, as shown in Table 1, compound F, compound G and compound H did not exhibit selectivity for c-MET and RON kinase, as reported IC's at 17nM, 2nM and 3nM, respectively, relative RON₅₀The values are confirmed. See table 1, below and the' 556 application, page 36. Then, as shown in Table 1, the conversion was made toFold selectivity for RON over MET kinase for compound F, compound G and compound H were 0.32, 0.04 and 0.75, respectively, indicating that compounds are more potent on RON kinase than MET kinase. In view of these data, the selectivity of compound D for these "off-target" kinases was unexpected. In short, it is hypothesized that the central benzene ring pair disubstituted pattern in combination with the pyridine ring acetamide moiety confers this unexpected MET potency and selectivity to these "off targets".

Without being bound by a particular theory, it is speculated that the presence of a central non-halogen R3 moiety on a heteroaromatic ring containing a monocyclic nitrogen works together with the para-disubstituted pattern of the central benzene ring to unexpectedly result in further improvements in potency and/or selectivity. In particular, one difference in the structures of compound D, compound G and compound H is the identity of the substituents in the pyridine ring. In compound D, the substituent is-NHC (O) CH3 (acetamide), while in compound G and compound H, the substituent is a more extended urea. In summary, it is speculated that the presence of a central benzene ring versus disubstituted pattern in combination with the combination of specific pyridine ring moieties (e.g., acetamide versus extended urea moieties) confers this unexpected c-MET potency and high selectivity towards these "off-targets". Other features that may also lead to the unexpected results described herein include: para-spatial relationship between the oxygen ether linkage and the nitrogen amide atom attached to the central benzene ring; para-spatial relationship between the oxygen ether linking atom and the ring nitrogen in the ring containing nitrogen; an alkyl spacer is absent between the aromatic ring and the nitrogen of the cyclopropanecarbonyl. Although cyclopropane amides are reported in the literature as inhibitors of c-MET kinase activity, no compounds with this characteristic have been disclosed as discussed above.

Equivalent forms

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific embodiments specifically described in this disclosure. Such equivalents are intended to be encompassed by the scope of the following claims.

Claims (18)

1. A compound of the formula I, wherein,

or a pharmaceutically acceptable salt thereof,

wherein

X is fluorine or chlorine;

z1 and Z2 are CR 2;

z3 is CH;

r1 is each independently and individually fluorine or H;

each R2 is independently and independently H;

r3 is-C (O) R4;

r4 is C3-C8 cycloalkyl, C1-C7 alkyl, - (CH)₂)_P-CN、-(CH₂)_p-OR6 OR- (CH)₂)_P-NR6(R7), wherein

Each alkyl or alkylene group being optionally substituted by one or two C1-C6 alkyl groups;

r6 and R7 are each independently and independently H or C1-C6 alkyl; and

p is 1,2 or 3.

2. The compound of claim 1, wherein the compound of formula (I) is a compound of formula Ic:

or a pharmaceutically acceptable salt thereof, and

wherein

n is 0, 1 or 2, and wherein R2 is H.

3. The compound of claim 2, wherein R4 is C3-C8 cycloalkyl or C1-C7 alkyl, and wherein each alkyl or alkylene is optionally substituted with one or two C1-C6 alkyl groups.

4. The compound of claim 1, which is:

n- (4- (2-acetamidopyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

n- (4- (2-acetamidopyridin-4-yloxy) -5-chloro-2-fluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

n- (4- (2-acetamidopyridin-4-yloxy) -2, 5-difluorophenyl) -N' -phenylcyclopropane-1, 1-dicarboxamide;

n- (4- (2- (2- (dimethylamino) acetamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

n- (4- (2- (cyclopropanecarboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

n- (2, 5-difluoro-4- (2-propionamido) pyridin-4-yloxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

n- (2, 5-difluoro-4- ((2- (2-methoxyacetamido) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

n- (2, 5-difluoro-4- (2-isobutyramidopyridin-4-yloxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

n- (4- (2- (2-cyanoacetamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

n- (4- (2- (cyclobutanecarboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

(R) -N- (2, 5-difluoro-4- ((2- (2-methoxypropionylamino) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

(R) -N- (2, 5-difluoro-4- ((2- (2-hydroxypropionamido) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

n- (2, 5-difluoro-4- ((2-pivaloylamidopyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

(S) -N- (2, 5-difluoro-4- ((2- (2-methoxypropionylamino) pyridin-4-yl) oxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

(S) -l- ((4- (2, 5-difluoro-4- (l- ((4-fluorophenyl) carbamoyl) cyclopropanecarboxamido) phenoxy) pyridin-2-yl) amino) -l-oxopropan-2-yl acetate;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, which is:

n- (4- (2- (cyclopropanecarboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

n- (2, 5-difluoro-4- (2-propionamidopyridin-4-yloxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide;

n- (2, 5-difluoro-4- (2-isobutyramidopyridin-4-yloxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide; or

N- (4- (2-acetamidopyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide,

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound of any one of claims 1-5 and a pharmaceutically acceptable carrier.

7. The composition according to claim 6, further comprising an additive selected from an adjuvant or a stabilizer, and the pharmaceutically acceptable carrier is selected from an excipient or a diluent.

8. Use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of: melanoma, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, or colon cancer.

9. The use of claim 8, wherein the compound is administered orally, parenterally, by inhalation, or subcutaneously.

10. The compound of claim 5 which is N- (4- (2- (cyclopropanecarboxamido) pyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising the compound of claim 10 and a pharmaceutically acceptable carrier.

12. The composition according to claim 11, further comprising an additive selected from an adjuvant or a stabilizer, and the pharmaceutically acceptable carrier is selected from an excipient or a diluent.

13. The compound of claim 5 which is N- (2, 5-difluoro-4- (2-propionamidopyridin-4-yloxy) phenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide or a pharmaceutically acceptable salt.

14. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable carrier.

15. The composition according to claim 14, further comprising an additive selected from an adjuvant or a stabilizer, and the pharmaceutically acceptable carrier is selected from an excipient or a diluent.

16. The compound of claim 5 which is N- (4- (2-acetamidopyridin-4-yloxy) -2, 5-difluorophenyl) -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising the compound of claim 16 and a pharmaceutically acceptable carrier.

18. The composition according to claim 17, further comprising an additive selected from an adjuvant or a stabilizer, and the pharmaceutically acceptable carrier is selected from an excipient or a diluent.