TW201629036A - Quinoline and quinazoline compounds - Google Patents

Abstract

In some embodiments, the invention relates to quinazoline and quinoline compounds of Formula I: (I) or a pharmaceutically acceptable salt thereof, or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, in some embodiments, the present invention relates to quinazoline and quinoline compounds, pharmaceutical compositions thereof, and the use of the compounds and pharmaceutical compositions in the treatment of Bruton's tyrosine kinase (BTK) mediated disorders.

Description

Quinoline and quinazoline compounds

In some embodiments, the invention relates to heterocyclic compounds, pharmaceutical compositions comprising the compounds, and the use thereof. In some embodiments, the invention relates to the use of quinazoline and quinoline compounds for the treatment of Bruton's tyrosine kinase (BTK) vector disorder.

Activation of B lymphocytes is critical in the development of adaptive immune responses. Detuned B lymphocyte activation is a hallmark of many immune diseases, so the regulation of this immune response is of medical concern. Recently, the success of B cell therapy for autoimmune diseases has been established. Treatment of patients with rheumatoid arthritis (RA) with rituximab (anti-CD20 therapy) is a recognized clinical therapy. More recent clinical trials have shown that treatment with rituximab can also ameliorate disease symptoms in patients with relapsing-remitting multiple sclerosis (RRMS) and systemic lupus erythematosus (SLE). This success supports the possibility of future therapies for autoimmune diseases that target B cell immunity.

Bruton's tyrosine kinase (BTK) is a Tec family non-receptor protein kinase expressed in B cells and bone marrow cells. The function of BTK in the signal transduction pathway activated by the engagement of B cell receptor (BCR) and FcεR1 on obese cells is well established. In addition, the function of BTK as a downstream target in Toll-like receptor signaling is proposed. BTK is homologous (pleckstrin homology, PH), Tec homology (TH), Src homology 3 (SH3), Src homology 2 (SH2), and tyrosine kinase or Src homology. 1 (TK or SH1) domain consists of. The function of BTK in the signal transduction pathway activated by the engagement of B cell receptor (BCR) in mature B cells and FCER1 on obese cells is well established. Functional mutations in BTK in humans lead to primary immunodeficiency disease (X-linked agammaglobuinaemia), which develops in progenitor B cells (pro-B cells) with B cells. Defects that cause blockage between pre-B cell stages are characteristic. The result is an almost complete lack of B cells, resulting in a significant reduction in serum immunoglobulins of all classes. These findings support the pivotal role of BTK in the regulation of autoantibody production of autoimmune diseases.

BTK is expressed in many B cell lymphomas and leukemias. Other diseases in which dysfunctional B cells play an important role are B cell malignancies, as described in Hendriks, et al. , Nat . Rev. Cancer , 2014, 14, 219-231. The reported role of BTK in the regulation of B cell proliferation and apoptosis shows the possibility of BTK inhibitors in the treatment of B cell lymphoma. Therefore, BTK inhibitors have been developed as potential therapies for many of these malignancies, as described in D'Cruz, et al. , OncoTargets and Therapy 2013, 6, 161-176. BTK inhibitors may also demonstrate the possibility of treating allergic reactions with the regulatory role reported by BTK in the activation of FcεR vector obese cells, as described in Gilfillan, et al. , Immunologic. Rev. 2009, 288, 149-169. Said. In addition, BTK has also been reported to be involved in RANKL-induced osteoclast differentiation, as described in Shinohara, et al. , Cell 2008, 132, 794-806, and thus may also be of interest for the treatment of bone resorption disorders. . Other diseases in which dysfunctional B cells play an important role are B cell malignancies. In fact, anti-CD20 therapy is effectively used clinically to treat follicular lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia, as in Lim, et al. , Haematologica , 2010, 95, 135- Said in 143. The reported role of BTK in the regulation of B cell proliferation and apoptosis has shown the potential for BTK inhibitors to treat B cell lymphoma. The inhibition of BTK appears to be particularly relevant to B cell lymphoma due to chronic active BCR signaling, as described in Davis, et al. , Nature , 2010, 463, 88-94.

In many solid tumors, the supporting microenvironment, which constitutes the majority of the tumor mass, is the driving force for tumor survival. The tumor microenvironment is usually defined as a complex mixture of "cells, soluble factors, signaling molecules, extracellular matrices, and mechanical codes" that promote tumor deformation, support tumor growth and invasion, protect tumors from host immunity, and culture treatment. Resistant, and provides a niche that is advantageous to metastasize, as described in Swartz, et al. , Cancer Res. , 2012, 72, 2473. Although tumors exhibit antigens that should be recognized by T cells, the role of tumor clearance by the immune system is rare because immunity is inhibited by the microenvironment. The treatment of tumor cells by, for example, chemotherapy has also proven insufficient to overcome the protective effects of the microenvironment. Therefore, there is an urgent need to consider new methods of microenvironment to more effectively treat solid tumors.

Some of the BTK inhibitors reported so far are not selective for Src family kinases. With the knockout of Src family kinases, particularly the dramatic adverse effects reported by double and triple knockouts, this is seen as a hindrance to the development of BTK inhibitors that are not selective for Src family kinases. Both Lyn-deficient and Fyn-deficient mice exhibited autoimmune mimicking the phenotype of human lupus nephritis. In addition, Fyn-deficient mice also showed significant neurological deficits. Lyn knockout mice also showed an allergic phenotype, indicating that Lyn is a broad negative regulator by controlling cellular obesity cell reactivity and allergy-related traits, as in Odom, et al. , J. Exp. Med. Said in 2004, 199, 1491-1502. In addition, Lyn old knockout mice develop severe splenomegaly (enlarged marrow) and diffuse mononuclear leukocytes / macrophage tumor, as in Harder, et al., Immunity, 2001, 15, 603-615 in Said. These observations are consistent with the increase in highly reactive B cells, obese cells and bone marrow cells, and Ig concentrations observed in Lyn-deficient mice. Female Src knockout mice are infertile due to follicular development and decreased ovulation, as described in Roby, et al. , Endocrine , 2005, 26, 169-176. The double gene knockout Src-/-Fyn-/- and Src-/-Yes-/- show a severe phenotype with effects on movement and respiration. The triple gene knockout Src-/-Fyn-/-Yes-/- died on day 9.5 as shown by Klinghoffer, et al. , EMBO J. , 1999, 18, 2459-2471. In the double-removal of Src-/-Hck-/-, two-thirds of the mice died at birth, while the living mice developed osteopetrosis, extramedullary hematopoiesis, anemia, and leukopenia. As shown in Lowell, et al. , Blood , 1996, 87, 1780-1792. Thus, inhibitors that inhibit multiple or all kinases of Src family kinases can simultaneously cause severe adverse effects.

In one embodiment, the invention includes a compound of formula I: Or a pharmaceutically acceptable salt thereof, wherein: A is CH or N, provided that if B is N, then A is CH; B is CH or N, provided that if A is N, then B is CH; T is CH Or N; U is CH or N; V is NR ₅ , O, S, SO or SO ₂ ; W is CH, N, O or S; X is C(R ₆ ), N, O or S; Y is CH , N or a bond; Z is CH or N; provided that: 0, 2, and 2 atoms of W, X, and Y are simultaneously heteroatoms; - when one of the atoms selected from W, X, and Y is O or S, Other atoms selected from W, X, Y may not be O or S; - when Y is CH or N, then X is C(R ₆ ) or N, and W is CH or N; R ₁ is H, optionally through R ₇ or C (O) R ₇ substituent of (C _1-4) alkyl, or optionally substituted by R ₇ or C (O) R substitution of the ₇ (C _1-5) alkoxy or optionally substituted by a hydroxy or (C _1-4 )alkyl substituted O-(C _2-6 )heterocycloalkyl; R ₃ is H, optionally substituted by R ₇ (C _1-3 )alkyl, or optionally R ₇ substituent of (C _3-7) cycloalkyl; R ₄ is _{H, R 11 C (O)} , R 12 S (O), R 13 SO 2, or optionally substituted by the R ₁₄ (C _{1- 6} ) an alkyl group; R ₁ and R ₃ may together form a (C _2-6 )heterocycloalkyl group; R ₅ is H or (C _1-3 )alkyl; R ₂ is H, halogen, cyano, (C _1-4 ) alkyl group, (C _{2 -4} ) alkenyl, (C _2-4 )alkynyl, (C _1-3 )alkoxy, (C _3-6 )cycloalkyl; all alkyl groups of R ₂ optionally pass through one or more halogen Substituted; or R ₂ is (C _6-10 )aryl or (C _2-6 )heterocycloalkyl; R ₆ is H or (C _1-3 )alkyl; or R ₂ and R ₆ may be taken together ( C _3-7 )cycloalkenyl, or (C _2-6 )heterocyclenyl; each optionally substituted by (C _1-3 )alkyl, or one or more halogen; R ₇ is H, (C _{1 -3} ) alkoxy, or (C _2-6 )heterocycloalkyl; (one or more) hydroxyl, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl Amino, (C _3-7 )cycloalkoxy; R _{11 is} independently selected from the group consisting of: (C _1-6 )alkyl, (C _2-6 )alkenyl, and (C _{2- 6} ) alkynyl wherein each alkyl, alkenyl or alkynyl group is optionally substituted with one or more groups selected from the group consisting of hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl , (C _1-3 ) alkoxy, (C _3-7 )cycloalkoxy, optionally substituted by hydroxy, halogen, or (C _1-3 )alkoxy[(C _1-4 )alkyl ] group, optionally substituted by hydroxy, halo, or (C _1-3) alkoxy-substituted bis [(C _1-4) alkyl] amino, (C _6-10) aryl, or (C _{3- 7} ) heterocycloalkyl, or R ₁₁ is a (C _1-5 )heteroaryl group optionally substituted with one or more groups selected from a halogen or a cyano group.

R ₁₂ and R _{13 are} independently selected from the group consisting of (C _2-6 )alkenyl or (C _2-6 )alkynyl, both optionally via one or more groups selected from the group consisting of Substitution: hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl]amine, (C _1-3 ) alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl, or (C _3-7 )heterocycloalkyl; or optionally one or more a (C _1-5 )heteroaryl group substituted with a group selected from halogen or cyano; R _{14 is} independently selected from the group consisting of halogen, cyano, or (C _2-6 )alkenyl or ( C _2-6 ) alkynyl, both optionally substituted by one or more groups selected from the group consisting of hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 ) alkyl]amino, bis[(C _1-4 )alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 An aryl group, a (C _1-5 )heteroaryl group or a (C _3-7 )heterocycloalkyl group.

While the preferred embodiment of the invention has been shown and described, it is intended to Various alternatives to the described embodiments of the invention can be used to operate the invention.

Unless otherwise defined, all technical and scientific terms used in this context have the same meaning meaning meaning All patents and publications mentioned in this application are hereby incorporated by reference in their entirety.

The terms "co-administration," "co-administering," "administered in combination with," and "in combination with" are used in this case. (administering in combination with)" includes administering two or more agents to an individual such that the two or more agents and/or their metabolites are simultaneously present in the individual. Co-administration includes simultaneous administration of individual compositions, individual compositions Administration at different times, or administration of two or more agents, in a composition.

The term "effective amount" or "therapeutically effective amount" means that the compound or combination of compounds described herein is sufficient to achieve the desired application including, but not limited to, the amount of disease treatment. The therapeutically effective amount depends on the intended application (in vitro or in vivo), or the individual to be treated and the disease (eg, the weight, age, and surname of the individual), the severity of the disease, the manner of administration, and the like, which may be This artist can easily decide. The term is also applied to a dose that induces a specific response in a target cell (eg, a decrease in platelet adhesion and/or cell migration). Regardless of whether the compound is administered in combination with other compounds, the timing of administration, The tissue to be administered, and the physical delivery system carrying the compound, will depend on the particular compound selected and the dosage regimen to be followed.

The term "therapeutic effect" when used in this context encompasses the therapeutic benefit and/or prophylactic benefit as described above. Prophylactic effects include delaying or excluding the occurrence of a disease or condition, delaying or eliminating the onset, slowing, termination, or reversal of the progression of a disease or condition, or any combination thereof.

The term "pharmaceutically acceptable salt" means a salt derived from organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, lauric acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In selected embodiments, the pharmaceutically acceptable base addition salt is selected from the group consisting of ammonium, potassium, sodium, calcium and magnesium salts. The term "cocrystal" means a molecular complex derived from some co-crystal formers known in the art. Unlike salt, co-crystals typically do not contain hydrogen transfer between the co-crystal and the drug, but instead contain intermolecular interactions such as hydrogen between the co-crystal former and the drug in the crystalline structure. Bonding, aromatic ring stacking, or dispersing force.

"Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. The use of such media and chemical agents for pharmaceutically active substances is well known in the art. The use of any conventional medium or chemical agent in the therapeutic compositions of the present invention is contemplated unless it is not compatible with the active ingredient. The supplemental active ingredient can also be incorporated into the composition.

"Prodrug" is intended to describe a compound which can be converted under physiological conditions or converted to a biologically active compound as described in the case by solvolysis. Thus, the term "prodrug" means a precursor to a biologically active compound which is pharmaceutically acceptable. Prodrugs can be inactive when administered to an individual, but are converted to the active compound in vivo, for example, by hydrolysis. Prodrug compounds generally provide advantages in solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgaard, Design of Prodrugs, Elsevier, Amsterdam, 1985). The term "prodrug" is also intended to include any covalently bonded carrier which, when administered to an individual, releases the active compound in vivo. Prodrugs of the active compounds as described herein may be prepared by modifying the functional groups present in the active compound such that the modifications are conventionally treated or cleaved in vivo to yield the active parent compound. Prodrugs include, for example, compounds wherein a hydroxy, amine or sulfhydryl group is bonded to any group, and when the active compound is administered to a mammalian individual, it is cleaved to form a free hydroxyl group, a free amine group, or a free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetates, formates and benzoate derivatives of alcohols in active compounds, and various ester derivatives of carboxylic acids. An amine, a carbamide, and a benzamide derivative of an amine or an amine functional group.

The term "in vivo" means an event that occurs in an individual's body.

The term "in vitro" means an event that occurs outside the body of an individual. In vitro assays encompass cell-based assays in which live or dead cells are used, and cell-free assays can also be included, in which intact cells are not used.

Unless otherwise specified, the chemical structures described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds in which one or more hydrogen atoms are replaced by deuterium or tritium or in which one or more carbon atoms are replaced by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of the invention.

Combinations and sub-combinations of the scope and the specific embodiments of the present invention are intended to be included in the scope of the present invention. When referring to a numerical or numerical range, the term "about" means an approximation of the range of experimental variation (or within the range of statistical experimental error), such that the numerical or numerical range can be, for example, 1% of the stated range of numbers or numbers 15% change. The term "comprising" (and its related terms such as "comprise" or "comprises" or "having" or "including" includes the embodiments, such as " An embodiment of any substance composition, method, or process that consists of (the features) or "consisting essentially of (the features)".

"Alkyl" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, free of unsaturation, having from one to ten carbon atoms (eg (C ₁ - ₁₀ ) alkyl or C ₁ - ₁₀ alkane) base). Whenever it appears in the present case, a numerical range such as "1 to 10" means each integer within a given range - for example "1 to 10 carbon atoms" means that the alkyl group may be 1 carbon atom, 2 The carbon atom, three carbon atoms, and the like, up to and including 10 carbon atoms, is also intended to cover the occurrence of the term "alkyl" when the numerical range is not specifically indicated. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, butyl isobutyl, tert-butyl, pentyl, iso Amyl, neopentyl, hexyl, heptyl, octyl, decyl and decyl. The alkyl moiety may be attached to the remainder of the molecule by a single bond, such as methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, N-pentyl, 1,1-dimethylethyl (tertiary butyl) and 3-methylhexyl. Unless otherwise specified in the patent specification, the alkyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkane , aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N _{^{(R a) 2, N (}} R a) C (NR a) N (R a) 2, -N (R a) S (O) t R a ( where t is 1 or 2), - S (O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , wherein R ^{a is} each independently hydrogen Alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

"Alkylaryl" means an -(alkyl)aryl group wherein the aryl and alkyl are as disclosed in the present disclosure and which are optionally substituted with one or more substituents which are used as a separate Suitable substituents for the base and alkyl group.

"Alkylheteroaryl" means an -(alkyl)heteroaryl group wherein the heteroaryl and alkyl are as disclosed in the present disclosure and are optionally substituted with one or more substituents as are respectively Suitable substituents for aryl and alkyl groups.

"Alkylheterocycloalkyl" means an -(alkyl)heterocyclyl wherein alkyl and heterocycloalkyl are as disclosed in the present disclosure and are optionally substituted with one or more substituents which are substituted As described above for the respective substituents of the heterocycloalkyl group and the alkyl group.

The "alkenyl" moiety means a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and the "alkyne" moiety means consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Group. Whether saturated or unsaturated, the alkyl moiety can be branched, straight chain, or cyclic.

"Alkenyl" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (ie (C ₂ - ₁₀ ) alkenyl or C _{2 -10} alkenyl). Whenever it appears in the present case, a numerical range such as "2 to 10" means each integer within a given range - for example "2 to 10 carbon atoms" means that the alkenyl group may be 2 carbon atoms, 3 Carbon atoms and the like, up to and including 10 carbon atoms. The alkenyl moiety can be attached to the remainder of the molecule by a single bond, such as vinyl (ie, vinyl), prop-1-enyl (ie, allyl), but-1-enyl, pent-1-ene And pentane-1,4-dienyl. Unless otherwise specified in the patent specification, alkenyl is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkane , aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N (R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , wherein R ^{a is} each independently hydrogen Alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

"Alkenyl-cycloalkyl" means -(alkenyl)cycloalkyl, wherein alkenyl and cycloalkyl are as disclosed in the present disclosure and are optionally substituted with one or more substituents which are as Suitable for the appropriate substituents of alkenyl and cycloalkyl, respectively.

"Alkynyl" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, and having from two to ten carbon atoms (ie (C _{2 -10} ) alkynyl or C _{2 -10} alkynyl). Whenever it appears in the present case, a numerical range such as "2 to 10" means each integer within a given range - for example "2 to 10 carbon atoms" means that the alkenyl group may be 2 carbon atoms, 3 Carbon atoms and the like, up to and including 10 carbon atoms. An alkynyl group can be attached to the remainder of the molecule by a single bond, such as, for example, ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Unless specifically stated otherwise in the patent specification, an alkynyl group is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyldecyl, - OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O) N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , wherein R ^{a is} independently Hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

"Alkynyl-cycloalkyl" means -(alkynyl)cycloalkyl, wherein alkynyl and cycloalkyl are as disclosed in the present disclosure and are optionally substituted with one or more substituents which are as Suitable for the appropriate substituents of alkynyl and cycloalkyl, respectively.

"Carboxaldehyde" means a -(C=O)H group.

"Carboxy" means a -(C=O)OH group.

"Cyano" means a -CN group.

"Cycloalkyl" means a monocyclic or polycyclic radical containing only carbon and hydrogen and which may be saturated or partially unsaturated. The cycloalkyl group includes a group having 3 to 10 ring atoms (that is, a (C ₃ - ₁₀ ) cycloalkyl group or a C ₃ - ₁₀ cycloalkyl group). Whenever it appears in the present case, a numerical range such as "3 to 10" means each integer within a given range - for example "3 to 10 carbon atoms" means that the cycloalkyl group may be 3 carbon atoms, etc. Up to and including 10 carbon atoms. Illustrative examples of cycloalkyl include, but are not limited to, the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, Cyclodecyl, cyclodecyl, thiol and the like. Unless otherwise specified in the patent specification, a cycloalkyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S( O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , wherein R ^{a is} independently It is hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

"Cycloalkyl-alkenyl" means -(cycloalkyl)alkenyl, wherein cycloalkyl and alkenyl are as disclosed in the present disclosure and are optionally substituted with one or more substituents which are as Used as appropriate for the appropriate substituents of cycloalkyl and alkenyl groups, respectively.

"Cycloalkyl-heterocycloalkyl" means -(cycloalkyl)heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are as disclosed in the present disclosure and optionally substituted with one or more substituents Substituted, the substituents are as described for the appropriate substituents for the cycloalkyl and heterocycloalkyl groups, respectively.

"Cycloalkyl-heteroaryl" means a -(cycloalkyl)heteroaryl group, wherein Cycloalkyl and heteroaryl are as disclosed in the present disclosure and are optionally substituted with one or more substituents as described for the appropriate substituents for cycloalkyl and heteroaryl, respectively.

The term "alkoxy" means an -O-alkyl group, including straight chain, branched chain, cyclic configurations of from 1 to 8 carbon atoms, and combinations thereof, attached to the parent structure via oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, and cyclohexyloxy. "Lower alkoxy" means an alkoxy group containing from one to six carbons.

The term "substituted alkoxy" means an alkoxy group wherein the alkyl component is substituted (ie, -O-(substituted alkyl)). Unless otherwise specified in the patent specification, the alkyl portion of the alkoxy group is optionally substituted with one or more substituents which are, independently, alkyl, heteroalkyl, alkenyl, alkynyl, cyclic Alkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl Base alkyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O) N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2) , -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , where R ^a each independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroaryl alkyl.

The term "alkoxycarbonyl" means a radical of the formula (alkoxy) (C=O)-, attached via a carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus, the (C ₁ - ₆ ) alkoxycarbonyl group is an alkoxy group having 1 to 6 carbon atoms, which is bonded to the carbonyl linking group via its oxygen. "Lower alkoxycarbonyl" means an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group.

The term "substituted alkoxycarbonyl" means a (substituted alkyl)-OC(O)- group in which the group is attached to the parent structure via a carbonyl functional group. Unless otherwise specified in the patent specification, the alkyl portion of the alkoxycarbonyl group is optionally substituted with one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, ring Alkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl Base alkyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O) _{^{N (R a) 2, -C}} (O) N (R a) 2, -N (R a) C (O) OR a, -N (R a) C (O) R a, -N (R a C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2) , -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , where R ^a each independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroaryl alkyl.

"Mercapto" means (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O) - and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure via a carbonyl functional group. If the R group is heteroaryl or heterocycloalkyl, the heterocyclic or chain atom constitutes the total number of chains or ring atoms. Unless otherwise specified in the patent specification, the alkyl, aryl or heteroaryl portion of the fluorenyl group is optionally substituted with one or more substituents independently of: alkyl, heteroalkyl, alkene , alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy , nitro, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (wherein t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, hetero Aryl or heteroarylalkyl.

"Alkoxy" means an R(C=O)O- group, wherein "R" is alkyl, aryl, heteroaryl, heteroalkyl or heterocycloalkyl, as described herein. . If the R group is heteroaryl or heterocycloalkyl, the heterocyclic or chain atom constitutes the total number of chains or ring atoms. Unless otherwise specified in the patent specification, the "R" of the methoxy group is optionally substituted with one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cyclic Alkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyl Base alkyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O) N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2) , -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , where R ^a each independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroaryl alkyl.

"Amine" or "amine" means ^a radical -N(R ^a ) ₂ wherein R ^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbon, unless otherwise specifically indicated in the patent specification. Cycloalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl. When -N (R ^a) ₂ group has two substituents other than hydrogen R ^a group, their may be combined with the nitrogen atom to form a 5, 6 or 7-membered ring. For example, -N(R ^a ) _{2 is} intended to include, but is not limited to, 1-pyrrolidinyl and 4- Alkyl group. Unless otherwise specified in the patent specification, the amine group is optionally substituted with one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyldecyl, - OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O) N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , wherein R ^{a is} independently Hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term "substituted amino group" also means -NHR ^d , and N-oxide of NR ^d R ^d , each as described above. The N-oxide can be prepared by treating the corresponding amine group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.

"Indoleamine" or "nonylamine" means a chemical moiety having the formula -C(O)N(R) ₂ or -NHC(O)R, wherein R is selected from the group consisting of hydrogen, alkyl , cycloalkyl, aryl, heteroaryl (via ring carbon bonding) and heteroalicyclic (via ring carbon bonding), these chemical moieties themselves can be optionally substituted. Amides of -N (R) R ₂ may be optionally formed of _2, 5, 6 or 7-membered ring together with the nitrogen to which they are attached. Unless otherwise specified in the patent specification, the guanamine group is optionally used independently for one or more of the alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups as described herein. Substituent substitution. The guanamine can be an amino acid or peptide molecule attached to a compound disclosed herein to form a prodrug. The steps and specific groups for making such guanamine are known to those skilled in the art and are readily found in developmental sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated by reference in its entirety for reference.

"Aromatic" or "aryl" or "Ar" means an aromatic radical having from six to ten ring atoms (eg, C ₆ -C ₁₀ aromatic or C ₆ -C ₁₀ aryl) having at least one of A ring of a conjugated π-electron system which is a carbocyclic ring (e.g., phenyl, anthracenyl, and naphthyl). A divalent group formed of a substituted benzene derivative and having a free valence in a ring atom is named as a substituted phenyl group. A monovalent polycyclic hydrocarbon group having a "-group" at the end of the name is a divalent group derived by removing a hydrogen atom from a carbon atom having a free valence by adding "-idene" to the corresponding monovalent group. The name is given up, for example, naphthyl with two attachment points is called naphthylidene. Whenever it appears in the present case, a numerical range such as "6 to 10" means each integer within a given range - for example "6 to 10 ring atoms" means that the aryl group may be 6 ring atoms, 7 A ring atom, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (ie, a ring that shares a pair of adjacent ring atoms). Unless otherwise specified in the patent specification, the aryl moiety is optionally substituted with one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, hetero Cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S( O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , wherein R ^{a is} independently It is hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

"Aralkyl" or "arylalkyl" means (aryl)alkyl wherein aryl and alkyl are as disclosed in the present disclosure and are optionally substituted with one or more substituents which are substituted As described for the appropriate substituents for the aryl group and the alkyl group, respectively.

"Ester" means a chemical group of the formula -COOR wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (via ring carbon bonding) and heteroalicyclic ( bonded via a ring carbon). the manufacturing steps and the specific ester groups known to skilled artisans and can be readily found in the development of sources such as Greene and Wuts, Protective groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is hereby incorporated by reference in its entirety in its entirety in its entirety in its entirety in the the the the the the the the the the Base, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl group, a trifluoromethoxy group, a nitro group, an alkyl trimethyl ^{silicon, -OR a, -SR a, -OC} (O) -R a, -N (R a) 2, -C (O) R a, -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a C(O)R ^a , -N(R ^a )C(O)N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S( O) _t R ^a (where t is 1 or 2), -S ( O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , wherein R ^{a is} independently It is hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

"Fluoroalkyl" means an alkyl group as defined above which is substituted with one or more fluoro groups as defined above. For example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl portion of the fluoroalkyl group can be optionally substituted as defined above for the alkyl group.

"Halo", "halide" or "halogen" is intended to mean fluoro, chloro, bromo or iodo. The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures via one or more halo or via Replaced by its combination. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy, respectively, wherein halo is fluoro.

"Heteroalkyl", "heteroalkenyl" and "heteroalkynyl" include optionally substituted alkyl, alkenyl and alkynyl groups and have one or more backbone chain atoms selected from non-carbonaceous Atoms such as oxygen, nitrogen, sulfur, phosphorus or combinations thereof. The numerical range can be given - for example a C ₁ -C ₄ heteroalkyl group, which means the total chain length, which in this example is 4 atoms long. Heteroalkyl groups may be substituted by one or more substituents which are, independently, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, Heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, pendant oxy, pendant thio, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N(R ^a ) ₂ , N(R ^a )C( NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), - S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , wherein each R ^{a is} independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbon Cycloalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

"Heteroalkylaryl" means a -(heteroalkyl)aryl group, wherein heteroalkyl and aryl are as disclosed in the present disclosure and are optionally substituted with one or more substituents as are respectively Suitable substituents for heteroalkyl and aryl groups.

"Heteroalkylheteroaryl" means a -(heteroalkyl)heteroaryl group wherein heteroalkyl and heteroaryl are as disclosed in the present disclosure and are optionally substituted with one or more substituents which are substituted The radicals are as described for the appropriate substituents for the heteroalkyl and heteroaryl groups, respectively.

"Heteroalkylheterocycloalkyl" means -(heteroalkyl)heterocycloalkyl, wherein heteroalkyl and heterocycloalkyl are as disclosed in the present disclosure and are optionally employed Substituted by one or more substituents as described for the appropriate substituents of heteroalkyl and heterocycloalkyl, respectively.

"Heteroalkylcycloalkyl" means a -(heteroalkyl)cycloalkyl group wherein heteroalkyl and cycloalkyl are as disclosed in the present disclosure and which are optionally substituted with one or more substituents, the substitution The bases are as described for the appropriate substituents for the heteroalkyl and cycloalkyl groups, respectively.

"Heteroaryl" or "heteroaromatic" or "HetAr" means a 5-18 aromatic group (e.g., C ₅ -C ₁₃ heteroaryl group), which comprises one or more selected from nitrogen, oxygen and sulfur of Ring heteroatoms, and which may be monocyclic, bicyclic, tricyclic or tetracyclic systems. Whenever it appears in the present case, a numerical range such as "5 to 18" means each integer within a given range - for example "5 to 18 ring atoms" means that the aryl group may be 5 ring atoms, 6 Ring atoms and the like, up to and including 18 ring atoms. A divalent group derived from a monovalent heteroaryl group whose name is "-based" by a radical having a free radical is added to the corresponding monovalent group by a "-idene" The name is given up, for example, pyridyl having two points of attachment is called pyridylidene. The nitrogen-containing "heteroaromatic" or "heteroaryl" moiety means an aromatic group wherein at least one of the backbone atoms of the ring is a nitrogen atom. Polycyclic heteroaryl groups can be fused or non-fused. The hetero atom of the heteroaryl group is optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule via any atom of the ring. Examples of heteroaryl groups include, but are not limited to, azepanene, acridinyl, benzimidazolyl, benzindenyl, 1,3-benzodioxolyl, benzene Furanyl, benzo Azyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxenylene,benz[b][1,4] Base, 1,4-benzoic acid Alkyl, benzonaphthylfuranyl, benzo Azolyl, benzodioxolyl, benzodiazepine English, benzo Azolyl, benzopipetanyl, benzopipedone, benzofuranyl, benzofuranone, benzofurazyl, benzothiazolyl, benzothienyl, benzothieno[3, 2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2- a ]pyridyl, carbazolyl, Lolinyl, cyclopenta[ d ]pyrimidinyl, 6,7-dihydro-5 H -cyclopenta[4,5]thieno[2,3- d ]pyrimidinyl, 5,6-dihydrobenzo[ h, Quinazolinyl, 5,6-dihydrobenzo[ h ] Lolinyl, 6,7-dihydro-5 H -benzo[6,7]cyclohepta[1,2- c ]嗒 , dibenzofuranyl, dibenzothiophenyl, furyl, furazyl, furanone, furo[3,2- c ]pyridyl, 5,6,7,8,9,10-six Hydrocyclooctyl [ d ]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctane [ d ]嗒 , 5,6,7,8,9,10-hexahydrocyclooctyl [ d ]pyridyl, isothiazolyl, imidazolyl, oxazolyl, indolyl, oxazolyl, isodecyl, anthracene Ortholinyl, isoindolyl, isoquinolinyl, anthracene Basis Azyl, 5,8-methyl bridge-5,6,7,8-tetrahydroquinazolinyl, Pyridyl, 1,6- Pyridyl group, Diazolyl, 2-oxooxyazetidinyl, Azyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[ h ]quinazolinyl, 1-phenyl-1 H -pyrrolyl, brown Thiophene Base Base , acridinyl, fluorenyl, piperidyl, pyrrolyl, pyrazolyl, pyrazolo[3,4- d ]pyrimidinyl, pyridyl, pyrido[3,2- d ]pyrimidinyl, pyridine [3,4- d ]pyrimidinyl, pyridyl Base, pyrimidinyl, oxime Base, pyrrolyl, quinazolinyl, quin Polinyl, quinolyl, isoquinolyl, tetrahydroquinolyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5] Thieno[2,3- d ]pyrimidinyl, 6,7,8,9-tetrahydro 5 H -cyclohept [4,5]thieno[2,3- d ]pyrimidinyl, 5,6,7, 8-tetrahydropyrido[4,5- c ]嗒 Base, thiazolyl, thiadiazolyl, thiopyranyl, triazolyl, tetrazolyl, tri Yl, thieno [2,3- d] pyrimidinyl, thieno [3,2- d] pyrimidinyl, thieno [2,3- c] pyridyl, and thienyl. Unless specifically stated otherwise in the patent specification, the heteroaryl moiety is optionally substituted with one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, Heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, pendant oxy, pendant thio, trimethyldecyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O)N (R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , wherein R ^{a is} each independently hydrogen Alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

Substituted heteroaryl groups also include ring systems substituted with one or more oxide (-O-) substituents, such as pyridyl N-oxide.

"Heteroarylalkyl" means a moiety having an aryl moiety as described herein attached to an alkylene moiety as described herein, wherein the remainder of the linkage to the molecule is via an alkylene group.

"Heterocycloalkyl" means a stable 3 to 18 membered non-aromatic cyclic group containing from two to twelve carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Whenever it appears in the present case, the numerical range such as "3 to 18" means that each integer within a given range - for example "3 to 18 ring atoms" means that the heterocycloalkyl group may be composed of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. Unless otherwise specified in the patent specification, heterocycloalkyl groups are monocyclic, bicyclic, tricyclic or tetracyclic systems which may include fused or bridged ring systems. The hetero atom of the heterocycloalkyl group can be optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. Heterocycloalkyl groups are partially or fully saturated. A heterocycloalkyl group can be attached to the remainder of the molecule via any atom of the ring. Examples of such heterocycloalkyl groups include, but are not limited to, dioxolyl, thienyl [1,3]dithiaalkyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, iso Thiazolidine Azolidinyl, Lolinyl, octahydroindenyl, octahydroisoindolyl, 2-sided oxetyl 3-sided oxypermide 2-sided oxy group Olinyl group, 3-sided oxy group Lolinyl, 2-oxopiperidinyl, 2-sided oxypyrrolidinyl, Zyridinyl, piperidinyl, piperid Base, 4-piperidinone, pyrrolidinyl, pyrazolyl, Pyridyl, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thio Olinyl, thia Lolinyl, 2-sided oxythio Olinyl, 3-sided oxythio Lolinyl, 1-sided oxy-thio Lolinyl, and 1,1-di-oxy-thio Alkyl group. Unless otherwise specified in the patent specification, the heterocycloalkyl moiety is optionally substituted with one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl ,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, pendant oxy, pendant thio, trimethyl decyl, - OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -OC(O)N(R ^a ) ₂ , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -N(R ^a )C(O)R ^a , -N(R ^a )C(O) N(R ^a ) ₂ , N(R ^a )C(NR ^a )N(R ^a ) ₂ , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O _t OR ^a (where t is 1 or 2), -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), or PO ₃ (R ^a ) ₂ , wherein R ^{a is} independently Hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

"Heterocycloalkyl" also includes bicyclic systems wherein one non-aromatic ring (generally having 3 to 7 ring atoms) contains at least 2 carbon atoms and, in addition, 1-3 are independently selected from the group consisting of oxygen, sulfur, and a hetero atom of nitrogen and a combination comprising at least one of the foregoing heteroatoms; and the other ring (generally having 3 to 7 ring atoms) optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is non- Aromatic.

"Nitro" means -NO ₂ group.

"Oxa" means an -O- group.

"Sideoxy" means an =0 group.

"Isolators" are different compounds having the same molecular formula. "Stereoisomers" are those in which only atoms are arranged in space, that is, isomers having different stereochemical configurations. "Spiegelmer" is a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of mirror image isomers is a "racemic" mixture. The term "(±)" is used where appropriate to specify the racemic mixture. A "non-image isomer" is a stereoisomer having at least two asymmetric atoms, but which are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure mirror image isomer, the stereochemistry of each chiral carbon can be specifically specified by ( R ) or ( S ). The absolute configuration of an unknown analytical compound can be specified as (+) or (-) (right-handed or left-handed) depending on the direction of the plane-polarized light at the wavelength of the sodium D-line. Certain compounds described herein contain one or more asymmetric centers and are therefore capable of introducing mirror image isomers, non-image areomers, and other stereotypes which may be defined as ( R ) or ( S ) for absolute stereochemistry. Isomer. The chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. The optically active ( R )- and ( S )-isomers can be prepared using chiral synthetic components or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

As used herein, "mirroromer purity" means the relative amount of a particular mirror image isomer relative to other mirror image isomers, expressed as a percentage. For example, if a compound (which potentially has a ( R )- or ( S )-isomer configuration) exists as a racemic mixture, there is a mirror image of the ( R )- or ( S )-isomer The purity of the construct is about 50%. If one of the isomer forms of the compound has an advantage over the other, such as 80% ( S )-isomer and 20% ( R )-isomer, the compound has a mirror image of the ( S )-isomer form. The purity of the isomer was 80%. The purity of the image isomers of the compounds can be determined by methods known in the art, including chromatography using chiral supports, optical rotation measurements of polarized light rotation, use of chiral shift reagents (including those containing chiral complexes). Nuclear magnetic resonance spectroscopy of a family element or Pirkle's reagent, or derivatization of a compound using a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.

In a preferred embodiment, the enriched enantiomer composition has a higher potency than the racemic mixture of the composition in terms of medical use per unit mass. The mirror image isomers may be separated from the mixture by methods known to those skilled in the art including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred mirror isomers may be borrowed Made by asymmetric synthesis. See, for example, Jacques, et al. , Enantiomers, Racemates and Resolutions, Wiley Interscience, New York, 1981; Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, NY, 1962; and Eliel and Wilen, Stereochemistry of Organic Compounds, Wiley, New York, 1994.

As used herein, the terms "enriched mirror image isomer" and "non-racemic" mean a composition wherein the weight percent of one of the mirror image isomers is greater than the amount of one of the mirror image isomers in the controlled mixture of the racemic composition. (eg greater than 1:1 by weight). For example, an enriched mirror image isomer formulation of ( S )-mirrromer is meant to have greater than 50% by weight, such as at least 75% by weight, or such as at least 80% by weight of ( S )-mirrromer (relative to ( Formulation of R )-mirroromer. In some embodiments, the enrichment can be significantly greater than 80% by weight, providing a "substantially enriched mirror image isomer" or "substantially non-racemic" formulation, which means that the composition formulation has at least 85% by weight A mirror image isomer (relative to other mirror image isomers) such as at least 90% by weight, or such as at least 95% by weight. The term "mirrible isomer pure" or "substantially mirrored isomer pure" means that the composition comprises at least 98% of a single mirror image isomer and less than 2% of a relatively mirror image isomer.

"Moiety" means a specific fragment or functional group of a molecule. The chemical moiety is typically an approved chemical entity that is embedded in or attached to the molecule.

"Tautomers" are structurally distinct isomers that are converted to each other by tautomerization. "Tautomerization" is an isomerized form and includes prototropic or proton-shift tautomerization, which is considered to be a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-shift tautomerization" includes proton transfer accompanied by a change in bond level, usually the exchange of a bond with an adjacent double bond. When tautomerization is feasible (as in solution), the chemical equilibrium of the tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-ketene tautomerization is the mutual conversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerization is phenol-keto tauto isomerization. A specific example of phenol-keto tautomerization is the mutual conversion of pyridin-4-ol and pyridine-4(1 H )-one tautomer.

"Debonding radical or atom" is any radical or atom that will cleave from the starting material under the chosen reaction conditions, thereby promoting a reaction at a particular location. Unless otherwise specified, examples of such a group include a halogen atom and a methylsulfonyloxy group, a p-nitrobenzenesulfonyloxy group, and a tosyloxy group.

"Protecting group" is intended to mean a group that selectively blocks one or more reactive sites in a polyfunctional compound such that the chemical reaction is selectively carried out on other unprotected reactive sites and the group is It is then easily removed after the selective reaction is completed. Various protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York, 1999.

"Solvate" means a compound that is physically associated with one or more pharmaceutically acceptable solvent molecules.

"Substituted" means that the groups mentioned may be individually linked to one or more other groups, radicals or moieties and are independently selected from, for example, sulfhydryl groups, alkyl groups. , alkylaryl, cycloalkyl, aralkyl, aryl, sugar, alkyl, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio , cyano, halo, carbonyl, ester, thiocarbonyl, isocyanate, thiocyanate, isothiocyanate, nitro, pendant oxy, perhaloalkyl, perfluoroalkyl, phosphate, decyl, The sulfinyl, sulfonyl, sulfonyl, sulfoxyl, sulfonate, urea, and amine groups include mono- and disubstituted amine groups, and protected derivatives thereof. Substituents may be substituted, for example, a cycloalkyl substituent may have a halide substituent in one or more of its rings. The term "optionally substituted" means a random substitution by a specific group, radical or moiety.

"Sulfanyl" means a group which includes -S-(optionally substituted alkyl), -S-(optionally substituted aryl), -S-(optional substituted heteroaryl) And -S-(optional substituted heterocycloalkyl).

"Sulphalide" means a group which includes -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)- (optionally substituted amine) -S(O)-(optional substituted aryl), -S(O)-(optionally substituted heteroaryl) and -S(O)-(optional substituted heterocycloalkyl).

"Sulfo" refers to a group which includes -S(O ₂ )-H, -S(O ₂ )-(optionally substituted alkyl), -S(O ₂ )- (optional substituted amine) , -S(O ₂ )-(optional substituted aryl), -S(O ₂ )-(optional substituted heteroaryl), and -S(O ₂ )-(optional substituted) Cycloalkyl).

"Sulfonamidyl" or "sulfonamide" means a -S(=O) ₂ -NRR group, wherein each R is independently selected from the group consisting of hydrogen, alkyl , cycloalkyl, aryl, heteroaryl (bonded via a ring carbon) and heteroaliphatic (bonded via a ring carbon). The R group in the -S(=O) ₂ -NRR group -NRR may form a 4, 5, 6 or 7 membered ring together with the nitrogen to which it is attached. The sulfonamide group is optionally substituted with one or more substituents respectively for the alkyl group, the cycloalkyl group, the aryl group, and the heteroaryl group.

"sulfoxyl" means a -S(=O) ₂ OH group.

"Sulfonate" means a -S(=O) ₂ -OR group wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl via ring carbon linkages and Aliphatic group (bonded via a ring carbon). The sulfonic acid group is optionally substituted on R with one or more substituents respectively for the alkyl, cycloalkyl, aryl, heteroaryl group.

The compounds of the invention also include crystalline and amorphous forms of the compounds, including, for example, polymorphs of the compounds, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrous , a configuration of a polymorph, and an amorphous form, and mixtures thereof. Unless specifically mentioned in the crystalline or amorphous form, "crystalline form" and "polymorph" are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, Polymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, and mixtures thereof.

BTK inhibitor

BTK inhibitors of the invention can include BTK inhibitors that are covalently bound to a target (in an irreversible manner), and BTK inhibitors that are non-covalently bound to a target (in a reversible manner). In one embodiment, the BTK inhibitor is a compound of formula I:

Or a pharmaceutically acceptable salt thereof, wherein: A is CH or N, provided that if B is N, then A is CH; B is CH or N, provided that if A is N, then B is CH; T is CH Or N; U is CH or N; V is NR ₅ , O, S, SO or SO ₂ ; W is CH, N, O or S; X is C(R ₆ ), N, O or S; Y is CH , N or a bond; Z is CH or N; provided that: 0, 2, and 2 atoms of W, X, and Y are simultaneously heteroatoms; - when one of the atoms selected from W, X, and Y is O or S, Other atoms selected from W, X, Y may not be O or S; - when Y is CH or N, then X is C(R ₆ ) or N, and W is CH or N; R ₁ is H, optionally through R ₇ or C (O) R ₇ substituent of (C _1-4) alkyl, or optionally substituted by R ₇ or C (O) R substitution of the ₇ (C _1-5) alkoxy or optionally substituted by a hydroxy or (C _1-4 )alkyl substituted O-(C _2-6 )heterocycloalkyl; R ₃ is H, optionally substituted by R ₇ (C _1-3 )alkyl, or optionally R ₇ substituted by (C _3-7 )cycloalkyl; R ₄ is H, R ₁₁ C(O), R ₁₂ S(O), R ₁₃ SO ₂ , or optionally substituted by R ₁ 4 (C _{1 -6} )alkyl; R ₁ and R ₃ may together form a (C _2-6 )heterocycloalkyl group; R ₅ is H or (C _1-3 )alkyl; R ₂ is H, halogen, cyano, C _1-4 )alkyl, (C _2-4 ) alkenyl, (C _2-4 )alkynyl, (C _1-3 )alkoxy, (C _3-6 )cycloalkyl; all alkyl groups of R ₂ are optionally subjected to one or more Halogen substituted; or R ₂ is (C _6-10 ) aryl or (C _2-6 )heterocycloalkyl; R ₆ is H or (C _1-3 )alkyl; or R ₂ and R ₆ may be taken together (C _3-7 )cycloalkenyl, or (C _2-6 )heterocyclenyl; each optionally substituted by (C _1-3 )alkyl, or one or more halogen; R ₇ is H, (C _1-3 ) alkoxy group, or (C _2-6 )heterocycloalkyl group; (one or more) hydroxyl group, [(C _1-4 )alkyl]amino group, bis[(C _1-4 ) alkane Amino, (C _3-7 )cycloalkoxy; R _{11 is} independently selected from the group consisting of: (C _1-6 )alkyl, (C _2-6 )alkenyl, and (C _{2 -6} ) alkynyl, wherein each alkyl, alkenyl or alkynyl group is optionally substituted with one or more groups selected from the group consisting of hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkane group, (C _1-3) alkoxy, (C _3-7) cycloalkyl group, the optionally substituted by hydroxy, halo, or (C _1-3) alkoxy, [(C _1-4) alkyl A bis[(C _1-4 )alkyl]amino group, (C _6-10 ) aryl group or (C ₃ ) optionally substituted by a hydroxy group, a halogen, or a (C _1-3 ) alkoxy group _-7) heterocycloalkyl, R ₁₁ is those with one or more substituents selected from halogen or optionally the cyano group of (C _1-5) heteroaryl.

R ₁₂ and R _{13 are} independently selected from the group consisting of (C _2-6 )alkenyl or (C _2-6 )alkynyl, both optionally via one or more groups selected from the group consisting of Substitution: hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl]amine, (C _1-3 ) alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl, or (C _3-7 )heterocycloalkyl; or optionally one or more a (C _1-5 )heteroaryl group substituted with a group selected from halogen or cyano; R _{14 is} independently selected from the group consisting of halogen, cyano, or (C _2-6 )alkenyl or ( C _2-6 ) alkynyl, both optionally substituted by one or more groups selected from the group consisting of hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 ) alkyl]amino, bis[(C _1-4 )alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 An aryl group, a (C _1-5 )heteroaryl group or a (C _3-7 )heterocycloalkyl group.

In one embodiment, the BTK inhibitor is a compound of formula II:

All of the labels and groups are as defined above.

In one embodiment, the BTK inhibitor is a compound of formula III:

All of the labels and groups are as defined above.

In one embodiment, the BTK inhibitor is a compound of formula IV:

Or a pharmaceutically acceptable salt thereof, wherein: T is CH or N; U is CH or N; V is NR ₅ , O, S, SO or SO ₂ ; W is CH, N, O or S; X is C (R ₆ ), N, O or S; Y is CH, N or a bond; Z is CH or N; provided that: 0, 2, and 2 atoms of W, X, and Y are simultaneously heteroatoms; When one of the atoms of X and Y is O or S, the other atoms selected from W, X, and Y may not be O or S; - when Y is CH or N, then X is C(R ₆ ) or N, And W is CH or N; R ₁ is H, optionally substituted with R ₇ or C(O)R ₇ (C _1-4 )alkyl, or optionally substituted by R ₇ or C(O)R ₇ (C _1-5 ) alkoxy, or O-(C _2-6 )heterocycloalkyl optionally substituted by hydroxy or (C _1-4 )alkyl; R ₃ is H, optionally substituted by R ₇ a (C _1-3 )alkyl group, or a (C _3-7 )cycloalkyl group optionally substituted by R ₇ ; R ₄ is R ₁₁ C(O); R ₁ and R ₃ may be formed together (C _{2 6} ) a heterocycloalkyl group; R ₅ is H or (C _1-3 )alkyl; R ₂ is H, halogen, cyano, (C _1-4 )alkyl, (C _2-4 )alkenyl, ( C _2-4) alkynyl, (C _1-3) alkoxy, (C _3-6) cycloalkyl alkyl group; R ₂ lines of all alkyl groups optionally substituted by one or more halo; or R ₂ is ( C _6-10) aryl or (C _2-6) Cycloalkyl group; R ₆ is H or (C _1-3) alkyl; or R ₂ and R ₆ may together form a (C _3-7) cycloalkenyl, or (C _2-6) alkenyl heterocyclyl group; each Optionally substituted with (C _1-3 )alkyl, or one or more halogen; R ₇ is H, (C _1-3 ) alkoxy, or (C _2-6 )heterocycloalkyl; a plurality of) hydroxy, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl]amino, (C _3-7 )cycloalkoxy; R _{11 is} independently selected from ( The C _2-6 )alkenyl and (C _2-6 )alkynyl, alkenyl or alkynyl groups are each optionally substituted with one or more groups selected from the group consisting of hydroxy, (C _1-4 )alkyl, ( C _3-7 )cycloalkyl, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl, (C _3-7 )heterocycloalkyl, Optionally substituted by a hydroxy, halogen, or (C _1-3 ) alkoxy group of a [(C _1-4 )alkyl]amino group, optionally substituted by a hydroxy group, a halogen, or a (C _1-3 ) alkoxy group The second [(C _1-4 )alkyl]amino group.

Pharmaceutical composition

In selected embodiments, the invention provides for treatment A pharmaceutical composition of solid tumor cancer, lymphoma and leukemia.

The pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a BTK inhibitor, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, as an active ingredient. When necessary, the pharmaceutical composition contains a pharmaceutically acceptable salt and/or a complexing complex thereof, and one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents Including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants.

The pharmaceutical composition is administered as a BTK inhibitor. Other agents may be admixed into the formulation as needed or both components may be formulated as individual formulations for combined use either individually or simultaneously.

In selected embodiments, the concentration of the BTK inhibitor provided in the pharmaceutical composition of the present invention is independently less than, for example, 100%, 90%, 80%, 70%, 60, relative to the total mass or volume of the pharmaceutical composition. %, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05% , 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006 %, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v or v/v.

In the selected embodiment, the pharmaceutical composition of the present invention The concentration of the BTK inhibitor provided is independently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, respectively, relative to the total mass or volume of the pharmaceutical composition. 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75 %, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50 %, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% Or 0.0001% w/w, w/v, or v/v

In selected embodiments, the concentration of the BTK inhibitor of the present invention is independently from about 0.0001% to about 50%, from about 0.001% to about 40%, and about 0.01%, relative to the total mass or volume of the pharmaceutical composition. From about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19% From about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12% or about From 1% to about 10% w/w, w/v or v/v.

In selected embodiments, the concentration of the BTK inhibitor of the present invention is independently from about 0.001% to about 10%, from about 0.01% to about 5%, and about 0.02%, based on the total mass or volume of the pharmaceutical composition.约约约约约约约约约约约%, from about 0.09% to about 1%, from about 0.1% to about 0.9% w/w, w/v or v/v.

In selected embodiments, the amounts of the BTK inhibitors of the invention are each independently equal to or less than 3.0 grams, 2.5 grams, 2.0 grams, 1.5 grams, 1.0 grams, 0.95 grams, 0.9 grams, 0.85 grams, 0.8 grams, 0.75. Grams, 0.7 grams, 0.65 grams, 0.6 grams, 0.55 grams, 0.5 grams, 0.45 grams, 0.4 grams, 0.35 grams, 0.3 grams, 0.25 grams, 0.2 grams, 0.15 grams, 0.1 grams, 0.09 grams, 0.08 grams, 0.07 grams, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g , 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g or 0.0001 g.

In selected embodiments, the amounts of the BTK inhibitors of the invention are each independently greater than 0.0001 grams, 0.0002 grams, 0.0003 grams, 0.0004 grams, 0.0005 grams, 0.0006 grams, 0.0007 grams, 0.0008 grams, 0.0009 grams, 0.001 grams, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.008 g, 0.009 g, 0.0095 g 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 Grams, 0.095 grams, 0.1 grams, 0.15 grams, 0.2 grams, 0.25 grams, 0.3 grams, 0.35 grams, 0.4 grams, 0.45 grams, 0.5 grams, 0.55 grams, 0.6 grams, 0.65 grams, 0.7 grams, 0.75 grams, 0.8 grams, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, or 3 g.

The BTK inhibitors according to the invention are each effective over a wide range of dosages. For example, in the treatment of adults, a dose in the range of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg, and 5 to 40 mg per day is used as an example of a usable dosage. The precise dose will depend on the route of administration, the form in which the compound is administered, the sex and age of the subject to be treated, the weight of the subject to be treated, and the preferences and experience of the attending physician.

The following are non-limiting pharmaceutical compositions and methods of making the same.

Oral pharmaceutical composition

In selected embodiments, the present invention provides an oral pharmaceutical composition comprising a BTK inhibitor of Formula I and a pharmaceutical excipient suitable for oral administration.

In selected embodiments, the present invention provides a solid oral pharmaceutical composition comprising (i) an effective amount of a BTK inhibitor of formula I and (ii) a pharmaceutical excipient suitable for oral administration. In selected embodiments, the composition further comprises (iii) an effective amount of a fourth compound.

In selected embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral administration. The pharmaceutical composition suitable for oral administration of the present invention may be in a discrete dosage form such as a capsule, a cachet, or a tablet, or a liquid or aerosol spray containing each of a predetermined amount of the powder or the active ingredient in the granule, aqueous or non-aqueous. A solution or suspension in a liquid, an oil-in-water emulsion, or a water-in-oil liquid latex is present. These dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with a carrier which comprises one or more essential ingredients. In general, the compositions are prepared by mixing the active ingredient with liquid carriers or finely divided solid carriers, or both, if necessary, in which the product is subsequently formed into the desired formulation. For example, tablets may be prepared by compression or stamping with one or more accessory ingredients. Compressed tablets may be in the form of a free-flowing form such as a powder or granules, optionally excipients such as, but not limited to, binders, lubricants, inert diluents, and/or surfactants or dispersing agents Produced by compression in a suitable machine. Molded tablets may be made by molding a mixture of powdered compounds which have been moistened with an inert liquid diluent in a suitable machine.

Since water promotes the degradation of some compounds, the present invention further encompasses anhydrous pharmaceutical compositions and dosage forms. For example, in pharmaceutical technology, water (e.g., 5%) can be added to simulate long-term storage to determine characteristics such as the shelf life or stability of the formulation over time. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture containing components and low moisture or low humidity conditions. The pharmaceutical compositions and dosage forms of the invention containing lactose can be made anhydrous if it is expected to be substantially in contact with moisture and/or humidity during manufacture, packaging, and/or storage. Anhydrous pharmaceutical compositions can be prepared and stored to maintain anhydrous character. Thus, anhydrous compositions may be packaged using materials known to avoid exposure to water such that they may be included in a suitable prescription kit. Examples of suitable packaging include, but are not limited to, sealing foils, plastics, etc., unit dose containers, blister packs, and strip packs.

Each of the BTK inhibitors as active ingredients can be intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In the compositions for the preparation of oral dosage forms, any conventional pharmaceutical medium may be employed as a carrier, such as, for example, an oral liquid preparation (such as suspensions, solutions, and elixirs) or an aerosol such as water or glycols. , oils, alcohols, flavoring agents, preservatives, coloring agents, etc.; or if it is an oral solid preparation, carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, And disintegrants can be used, and lactose is not used in some embodiments. For example, suitable carriers include powders, capsules, and tablets, together with solid oral formulations. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques.

Adhesives suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gels such as acacia gum, sodium alginate, alginic acid, other alginic acids Salt, powdered tragacanth, guar gum, cellulose and its derivatives (such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone , methyl cellulose, pre-gelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, calcium carbonate (e.g., granules or powders), microcrystalline cellulose, powdered cellulose, polygluconate, kaolin, Mannitol, citric acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

Disintegrants can be used in the compositions of the present invention to provide tablet disintegration when exposed to an aqueous environment. Too much disintegrant may cause the tablet to disintegrate into the bottle. Too little may not be sufficient to cause disintegration, thus changing the rate and extent of release of the active ingredient from the dosage form. Thus, a sufficient amount of disintegrant that is not too little or too much to adversely alter the release of the active ingredient can be used to form a dosage form of the compounds disclosed herein. The amount of disintegrant used can vary depending on the formulation and the mode of administration, and can be readily recognized by one of ordinary skill in the art. From about 0.5 to about 15 weight percent of the disintegrant, or from about 1 to about 5 weight percent of the disintegrant can be used in the pharmaceutical composition. Disintegrators which may be used to form the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, sodium carboxymethylcellulose, crosslinked pyrrolidone, and polaklin Potassium (polacrilin potassium), sodium starch glycolate, potato Or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algains, other celluloses, gels or mixtures thereof.

Lubricants which may be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene. Alcohols, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (eg peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, oil Ethyl acetate, ethyl gold carbonate, agar, or a mixture thereof. Other lubricants include, for example, syloid silicone, agglomerated aerosols of synthetic vermiculite, or mixtures thereof. The lubricant can optionally be added in an amount of less than about 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desirably administered orally, the active ingredients necessary in the present invention may be combined with various sweet or flavoring agents, colorants or dyes and, if desired, emulsifiers and/or suspending agents, together with Diluents such as water, ethanol, propylene glycol, glycerin, and combinations thereof are combined.

The tablets may be uncoated or coated by known techniques to delay disintegration and absorption of the gastric gum and thus provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use can also be presented in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in the form of a soft gelatin capsule, wherein the active ingredient is with a water or oil medium, for example Mix with peanut oil, liquid paraffin or olive oil.

Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfaces Active agents, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be used, a mixture of lipophilic surfactants may be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

Suitable hydrophilic surfactants can generally have an HLB value of at least 10, while suitable lipophilic surfactants can generally have an HLB value of less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of a nonionic amphiphilic compound is a hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic and have greater solubility in oil, while surfactants with higher HLB values are more hydrophilic and larger in aqueous solutions. Solubility. Hydrophilic surfactants are generally considered to be compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds that are generally unsuitable for HLB values. Likewise, a lipophilic (i.e., hydrophobic) surfactant is a compound having an HLB value of equal to or less than about 10. However, the HLB value of the surfactant is only a rough guide for the general deployment of industrial, pharmaceutical and cosmetic latexes.

Hydrophilic surfactants can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid; fatty acids derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides Lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl phosphates; fatty acid salts; Sodium ester sulfonate; decyl lactate; single and diglyceride And diacetylated tartrate; succinic acid mono- and diglycerides; citric acid esters of mono- and diglycerides; and mixtures thereof.

Within the above group, ionic surfactants include, for example, lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; octyl succinate sulfonate Sodium; decyl lactate; mono- and di-acetylated tartaric acid mono- and diglycerides; succinic acid mono- and diglycerides; citric acid mono- and diglycerides; and mixtures thereof.

The ionic surfactant may be ionized form of lecithin, lysolecithin, phospholipid choline, phospholipid oxime ethanolamine, phospholipid glycerol, phosphatidic acid, phospholipid lysine, lysophosphatidylcholine, lysophospholipid oxime ethanolamine , lysophosphatidylcholine glycerol, lysophosphatidic acid, lysophosphatidylcholine, PEG-phospholipid, ethanolamine, PVP-phospholipid, ethanolamine, fatty acid decyl ester, stearin-2-lactate, stearin lactate, amber Acid monoglyceride, mono- and di-acetylated tartaric acid mono/diglyceride; citric acid mono/diglyceride, cholestyramine, hexanoate, caprylate, phthalate, laurate, meat Myristate, palmitate, oleate, ricinoleate, linolenate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, Octyl succinate sulfonate, laurel carnitine, palm scorpion carnitine, myristyl carnitine, and salts and mixtures thereof.

Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltosides; alkylthioglucosides; lauryl polyethylene glycol glycerides; polyoxyalkylene alkyl ethers such as polyethylene Glycol alkyl Ether; polyoxyalkylene phenol such as polyethylene glycol alkyl phenol; polyoxyalkylene phenolic fatty acid ester such as polyethylene glycol fatty acid monoester and polyethylene glycol fatty acid diester; polyethylene glycol glycerol fatty acid a polyglycerol fatty acid ester; a polyoxyalkylene sorbitan fatty acid ester such as a polyethylene glycol sorbitan fatty acid ester; a hydrophilic transester of a polyalcohol with at least one member of the group consisting of Chemical products: glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene blocks a copolymer; and a mixture thereof; a polyethylene glycol sorbitan fatty acid ester, and a hydrophilic transesterification product of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and Hydrogenated vegetable oil. The polyalcohol can be glycerin, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or sugar.

Other hydrophilic-nonionic surfactants include (non-limiting) PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate , PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate , PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glycerol trioleate , PEG-32 dioleate, PEG-20 glycerol laurate, PEG-30 glycerol laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glycerol oleate, PEG-30 glycerol laurate, PEG-40 glycerol laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 Castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 tannic acid / caprylic acid glyceride, PEG-8 capric acid / caprylic acid glyceride, polyglycerol-10 laurate PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soy sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, Polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, fertility Phenol PEG-100 succinate, PEG-24 cholesterol, polyglycerol-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 Nonylphenol series, PEG 15-100 octylphenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of illustration only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; Tertiary sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; mono- and diglycerol a lactic acid derivative of an ester; a hydrophobic transesterification product of a polyalcohol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; oil-soluble vitamins/vitamin derivatives; And mixtures thereof. Preferred lipophilic surfactants within this group include glycerin fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyalcohols with at least one member of the group consisting of : vegetable oil, hydrogenated vegetable oil, and triglyceride.

In one embodiment, the composition may include a solubilizing agent to ensure solubilization and/or dissolution of the present invention and to minimize precipitation of the present invention. This is especially important in compositions for parenteral use, such as injectable compositions. A solubilizing agent may also be added to increase the solubility of the hydrophilic drug and/or other components such as surfactants, or to maintain a stable or homogeneous composition or dispersion of the composition.

Examples of suitable solubilizing agents include, but are not limited to, the following: alcohols and polyalcohols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and isomers thereof, glycerin , pentaerythritol, sorbitol, mannitol, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose Derivatives, cyclodextrins and cyclodextrin derivatives; ethers having polyethylene glycol having an average molecular weight of from about 200 to about 6000 such as tetrahydrofurfuryl alcohol PEG ether (tetrahydrofuran polyglycol ether) or methoxy PEG; Amines and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkyl piperidine Ketones, N-alkyl caprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, triethyl citrate triacetate, acetamidine Tributyl citrate, triethyl citrate, oleate, ethyl octanoate, ethyl butyrate, triacetin, propylene glycol monoacetate, propane Diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solvating agents known in the art such as dimethyl Acetamide, dimethyl isosorbide, N-methylpyrrolidone, caprylic monoglyceride, diethylene glycol monoethyl ether, and water.

Mixtures of solubilizing agents can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl octanoate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrole Pyridone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, tetrahydrofuran polyglycol ether, diethylene glycol monoethyl ether, propylene glycol And dimethyl isosorbide. Particularly preferred solubilizing agents include sorbitol, glycerin, triacetin, ethanol, PEG-400, tetrahydrofuran polyglycol ether, propylene glycol.

The amount of the solvent to be included is not particularly limited. The amount of a given solubilizing agent can be limited to a biologically acceptable amount, which can be readily determined by the skilled artisan. In some cases, it may be advantageous to include a greater amount of solubilizing agent than a biologically acceptable amount, for example to maximize drug concentration, while an excess of solubilizing agent uses conventional techniques such as distillation prior to providing the composition to the patient. Or removed by evaporation. Thus, if present, the solubilizing agent can comprise 10%, 25%, 50%, 100% by weight or up to about 200% by weight of the combined weight of the drug and other excipients. A very small amount of a solubilizing agent such as 5%, 2%, 1% or less may be used if necessary. Typically, the solubilizing agent can be present in an amount from about 1% to about 100% by weight, more typically from about 5% to about 25% by weight.

The composition may further comprise one or more pharmaceutical additives and excipients. Such additives and excipients include, but are not limited to, debonding agents, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, supplements, fragrances, colorants, odorants , opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

Additionally, an acid or base can be incorporated into the composition to facilitate the process, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, Synthetic aluminum citrate, synthetic water calcite, magnesium aluminum hydride, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, hydroxymethylamine Methane (TRIS) and so on. Also suitable is a base which is a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid , formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, amber Salts of acid, citric acid, tartaric acid, thioglycolic acid, toluene sulfonic acid, uric acid, and the like. Salts of polyprotonic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation such as ammonium, alkali metal and alkaline earth metal. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid. , hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicyl Acid, stearic acid, succinic acid, citric acid, tartaric acid, thioglycolic acid, toluenesulfonic acid and uric acid.

Pharmaceutical composition for injection

In selected embodiments, the present invention provides a pharmaceutical composition for injection comprising a BTK inhibitor and a pharmaceutical excipient suitable for injection. The components and doses in the composition are as described in this case.

Wherein the composition of the present invention can be incorporated by injection into an aqueous or oily suspension, or a latex containing sesame oil, corn oil, cottonseed oil, or peanut oil, and an expectorant, mannitol, dextrose, Or sterile aqueous solutions, and similar pharmaceutical carriers.

Aqueous solutions in saline are also convenient for injection. Ethanol, glycerin, propylene glycol, and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin to maintain the desired particle size (in terms of dispersion) or by the use of surfactants. Prevention of the action of microorganisms can be achieved by antibacterial agents and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and sodium thiomersal.

Sterile injectable solutions are prepared by sterilizing the desired amount of the BTK inhibitor with the various other ingredients listed above in a suitable solvent (as desired). Generally, dispersions are prepared by dissolving the various bactericidal active ingredients in a sterile vehicle containing an aqueous dispersion medium and the other ingredients enumerated above. For the preparation of sterile powders for sterile injectable solutions, some of the desired preparation methods are spray drying, vacuum drying and The lyophilization technique results in the active ingredient powder plus any additional ingredients from previous sterile filtration solutions. Other lyophilized or spray dried formulations known to those skilled in the art may also be used in accordance with the present invention. Such formulations include those disclosed in U.S. Patent Nos. 5,908,826, 6,267,958, 7, 682, 609, 7, 592, 004, and 8, 298, 530, and U.S. Patent Application Publication No. 2010/0158925, the disclosure of which is incorporated herein by reference.

Locally delivered pharmaceutical composition

In some embodiments, the invention provides a transdermally delivered pharmaceutical composition comprising a BTK inhibitor and a pharmaceutical excipient suitable for transdermal delivery.

The compositions of the present invention may be formulated into solid, semi-solid, or liquid form preparations suitable for topical or tropical administration such as gels, water-soluble jelly, creams, lotions, suspensions, foams, powders. , pulp, ointment, solution, oil, paste, medicine, spray, latex, saline solution, a solution based on dimethyl hydrazine (DMSO). Generally, carriers of higher density provide extended areas of exposure to the active ingredient. In contrast, solution formulations provide immediate exposure of the active ingredient to selected areas.

The pharmaceutical composition may also comprise a suitable solid or gel phase carrier or excipient which is a compound which increases the penetration of the medical molecule or assists in the delivery of the medical molecule across the stratum corneum barrier barrier of the skin. Many of these penetration enhancing molecules are known to those trained in topical formulating. Examples of such carriers and excipients include, but are not limited to, humectants (eg, urea), glycols (eg, propylene glycol), alcohols (eg, ethanol), fatty acids (eg, oleic acid), watches Surfactant (such as isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, hydrazine, hydrazine (such as menthol), amines, guanamines, alkanes, alkanes Alcohols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

Another formulation used in the methods of the invention employs a transdermal delivery device ("patch"). This transdermal delivery patch can be used to provide a continuous or intermittent infusion of the BTK inhibitor in a controlled amount (with or without other agents).

The construction and use of transdermal patches for the delivery of pharmaceutical agents are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4, 992, 445, and 5, 001, 139, the disclosures of which are incorporated herein by reference. Such patches can be constructed for continuous, pulsatile, or desired delivery of the pharmaceutical agent.

Other pharmaceutical compositions

The pharmaceutical composition may also be pharmaceutically acceptable according to the composition described in the present invention and one or more suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal. Excipient preparation. The preparation of such pharmaceutical compositions is well known in the art. See, for example, Anderson, et al. , Handbook of Clinical Drug Data , Tenth Edition, McGraw-Hill, 2002; and Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, NY, 1990, each incorporating This case is for reference.

Administration of BTK inhibitors or pharmaceutical compositions of these compounds This can be achieved by any method capable of delivering the compound to the site of action. These methods include oral route, intraduodenal route, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (eg transdermal administration), rectal administration , delivered locally via a catheter or stent or via inhalation. Combinations of compounds can also be administered intramuscularly or intrathecally.

Parenteral administration forms include solutions or suspensions of the active compounds in sterile aqueous solutions such as aqueous propylene glycol or dextrose solutions. These dosage forms can be moderately buffered if desired.

The invention also provides kits. The kit includes each BTK inhibitor (alone or in combination in a suitable package), and the writing material can include a discussion of use, a discussion of clinical studies, and a list of side effects. Such kits may also include information such as scientific literature references, package inserts, clinical trial results, and summaries of these, etc., which indicate or establish the activity and/or advantages of the composition, and/or its instructions for administration , administration, side effects, drug interactions, or other information useful to health care providers. Such information can be benchmarked by various studies such as studies using experimental animals involving in vivo models and results from studies based on human clinical trials. The kit may further contain other agents. In selected embodiments, the BTK inhibitor and the agent are provided as individual compositions in individual containers within the kit. In selected embodiments, the BTK inhibitor and the agent are provided as a single composition in a container within the kit. Suitable packaging and other articles for use (e.g., measuring cups for liquid preparation, foils to minimize exposure to air, etc.) are known in the art and may be included in the kit. The set described in this case is available Should be, sold and/or marketed to health providers including physicians, nurses, pharmacists, pharmacy officials, etc. In the selected implementation, the kit can also be sold directly to the consumer.

Dosage and dosage regimen

The amount of BTK inhibitor administered will depend on the mammal being treated, the severity of the disorder or condition, the rate of administration, the configuration of the compound, and the discretion of the prescribing physician. However, the effective dose is in the range of from about 0.001 to about 100 mg per kilogram of body weight per day, such as from about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this corresponds to about 0.05 to 7 grams per day, such as from about 0.05 to about 2.5 grams per day. In some cases, dose values below the lower limit of the above range may be sufficient, while in other cases larger doses may be used without causing any harmful side effects - for example, by dividing a larger dose into smaller doses for a full day Cast.

In selected embodiments, the BTK inhibitor is administered in a single dose. Typically, this administration will be by rapid introduction of the agent by injection, such as by intravenous injection. However, other paths may be used as appropriate. A single dose of BTK inhibitor can also be used to treat acute conditions.

In selected embodiments, the BTK inhibitor is administered in a multiple dose regime. The administration may be about once, twice, three times, four times, five times, six times, or more than six times a day. Administration can be about once a month, once every two weeks, once a week, or every other day. In other embodiments, the BTK inhibitor is administered about once a day to about 6 times a day. In another embodiment, the administration of the BTK inhibitor lasts less than about 7 day. In still another embodiment, the continuous administration is greater than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous administration is achieved and maintained as needed.

The administration of the medicament of the present invention is sustainable as needed. In selected embodiments, the BTK inhibitor is administered for greater than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the BTK inhibitor is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In selected embodiments, the BTK inhibitor is chronically administered on an ongoing basis - for example, for the treatment of chronic effects.

An effective amount of a combination of BTK inhibitors can be administered in a single dose or multiple doses by any of the accepted pharmaceutical administration modes of similar efficacy, including rectal, buccal, intranasal, and transdermal routes, by intra-arterial injection. Intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or inhalation.

treatment method

In some embodiments, the invention relates to a method of treating a hyperproliferative disorder, an inflammatory disorder, an immune disorder, or an autoimmune disorder in a mammal comprising a therapeutically effective amount of a BTK inhibitor or a BTK inhibitor. An acceptable salt, ester, prodrug, co-crystal, solvate, or hydrate is administered to the mammal.

In some embodiments, the invention relates to a method of treating a hyperproliferative disorder in a mammal with a BTK inhibitor selected from the group consisting of bladder cancer, head and neck cancer, pancreatic ductal adenocarcinoma (PDA) ), pancreatic cancer, colon cancer, breast cancer, breast cancer, fiber meat Tumor, mesothelioma, renal cell carcinoma, lung cancer, thymoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymic carcinoma, brain cancer, squamous cell carcinoma, skin cancer, eye cancer, retina Blastoma, melanoma, intraocular melanoma, oral and oropharyngeal cancer, gastric cancer, stomach cancer, cervical cancer, head, neck, kidney cancer, kidney cancer, liver cancer, ovarian cancer, photo Adenocarcinoma, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immunodeficiency syndrome (AIDS)-related cancer (such as lymphoma and Kaposi's sarcoma), virus-induced cancer, glia Cell tumor, esophageal tumor, hematological tumor, primary central nervous system lymphoma, non-small cell lung cancer (NSCLC), chronic myeloid leukemia, diffuse large B-cell lymphoma (DLBCL), esophageal tumor, follicular central lymph Tumor, head and neck cancer, hepatitis C virus infection, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's lym Phoma), ovarian tumor, pancreatic tumor, renal cell carcinoma, small cell lung cancer, or stage IV melanoma. In selected embodiments, the present invention relates to methods of treating disorders such as hyperproliferative disorders with BTK inhibitors, including but not limited to cancers such as acute myeloid leukemia, thymus, brain, lung, Squamous cells, skin, eyes, retinoblastoma, intraocular melanoma, oral and oropharynx, bladder, stomach, stomach, pancreas, bladder, breast, cervix, head, neck, kidney , kidney, liver, ovary, prostate, colorectal, esophagus, testicular, gynecology, thyroid, central nervous system (CNS), peripheral nervous system (PNS), AIDS-related (eg lymphoma and Kaposi's sarcoma) ) Or viral-induced cancer. In some embodiments, the pharmaceutical composition is used to treat a non-cancer hyperproliferative disorder such as benign hyperplasia of the skin (eg, dryness), restenosis, or a line of care (eg, benign care line hypertrophy (BPH)).

In some embodiments, the invention relates to methods of treating inflammatory, immune, or autoimmune disorders in a mammal with a BTK inhibitor. In selected embodiments, the invention also relates to a method of treating a disease with a BTK inhibitor, wherein the disease is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, arteries. Contaminant cirrhosis, inflammatory bowel disease, skin diseases such as cognac, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma and melanoma, ulcerative colon Inflammation, atopic dermatitis, cystitis, spondylitis, uveitis, Behcets disease, rheumatic polymyalgia, giant cell arteritis, sarcoma-like disease, Kawasaki disease, juvenile Arthritis, suppurative sweat gland inflammation, Sjögren's syndrome, dry arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's Disease, lupus, and lupus Nephritis.

In some embodiments, the present invention relates to a method of treating a solid tumor cancer with a composition comprising a BTK inhibitor, wherein the dose is effective to inhibit the solid tumor cancer cell and at least one selected from the group consisting of Signaling between microenvironments: macrophages, mononuclear white blood cells, obese cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, bone marrow-derived suppressor cells, regulatory B cells, hooliganism White blood cells, dendritic cells, and fibroblasts. Yusho In selected embodiments, the present invention relates to a method for treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, and colorectal cancer using a BTK inhibitor, wherein the dose is effective to inhibit the Signaling between a solid tumor cancer cell and at least one microenvironment selected from the group consisting of macrophages, mononuclear leukocytes, obese cells, helper T cells, cytotoxic T cells, regulatory T cells, Natural killer cells, bone marrow-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts.

In some embodiments, the hyperproliferative disorder is a solid tumor cancer selected from the group consisting of bladder cancer, squamous cell carcinoma, head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, Colon cancer, breast cancer, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung cancer, thymoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, scale Cell carcinoma, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cancer, oropharyngeal cancer, gastric cancer, stomach cancer, cervical cancer, kidney cancer, kidney Cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immunodeficiency syndrome (AIDS)-related cancer (eg lymphoma and Kaposi's sarcoma), Virus-induced cancers such as cervical cancer (human papilloma virus), B-cell lymphoproliferative disease, nasopharyngeal carcinoma (EB virus), Kaposi's sarcoma, and primary exudative lymphoma (Kaposi's sarcoma herpes) Virus) (B hepatitis virus and hepatitis C), and T-cell leukemia (Human T cell leukemia virus -1), glial blastoma, esophageal cancer, head and neck Tumor, metastatic colon cancer, head and neck squamous cell carcinoma, ovarian tumor, pancreatic tumor, renal cell carcinoma, hematological tumor, small cell lung cancer, non-small cell lung cancer, stage IV melanoma, and glioma.

In some embodiments, the hyperproliferative disorder is a B cell hematological malignancy selected from the group consisting of: chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (small lymphocytic leukemia) (SLL), non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL) ), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Burkitt Burkitt's lymphoma, Waldeström's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, myelodysplatic syndromes Or myelofibrosis. In one embodiment, the invention relates to a method of treating cancer in a mammal, wherein the cancer is chronic myelocytic leukemia, acute myeloid leukemia, DLBCL (including activated B cells) ABC) and germinal center B-cell (GCB) subtype), follicle center lymphoma, Hodgkin's disease, multiple myeloma , Indolent non-Hodgkin's lymphoma, and mature B-cell ALL.

In some embodiments, the hyperproliferative disorder is a subtype of CLL. Some CLL subtypes have been characterized. CLL is usually classified by the mutation state of the immunoglobulin heavy chain variable region (IgV _H ) in leukemia cells. RNDamle, et al. , Blood 1999, 94, 1840-47; TJ Hamblin, et al. , Blood 1999, 94, 1848-54. Patients with IgV _H mutations typically have longer survival than patients without IgV _H mutations. The performance of ZAP70 (positive or negative) is also used to characterize CLL. LZ Rassenti, et al. , N. Engl. J. Med. 2004, 351, 893-901. Methylation of ZAP-70 in CpG3 is also used to characterize CLL, such as by pyrosequencing. R. Claus, et al. , J. Clin. Oncol. 2012, 30, 2483-91; JAWoyach, et al. , Blood 2014, 123, 1810-17. CLL is also classified by disease staging under the Binet or Rai guidelines. JLBinet, et al. , Cancer 1977, 40, 855-64; KRRai, T. Han, Hematol . Oncol. Clin. North Am. 1990, 4, 447- 56. Other common mutations such as 11q deletion, 13q deletion, and 17p deletion can be assessed using well-known techniques such as fluorescence in situ hybridization (FISH). In one embodiment, the invention relates to a method of treating human CLL, wherein the CLL is selected from the group consisting of IgV _H mutation-negative CLL, ZAP-70-positive CLL, ZAP-70 in CpG3 methylation CLL CD38-positive CLL, chronic lymphocytic leukemia characterized by 17p13.1 (17p) deletion, and CLL characterized by 11q22.3 (11q) deletion.

In some embodiments, the hyperproliferative disorder is CLL, wherein the CLL has undergone Richter's transformation. The method of evaluating Richter's transformation (also known as Richter's syndrome) is described in P. Jain and S. O'Brien, Oncology , 2012, 26, 1146-52. Richter's transformation is a subtype of CLL observed in 5-10% of patients. It involves the development of progressive lymphoma from CLL and generally has a poor prognosis.

In some embodiments, the hyperproliferative disorder is a CLL or SLL of the patient, wherein the patient is susceptible to lymphocytosis. In one embodiment, the invention relates to a method of treating a CLL or SLL in a patient, wherein the patient develops a lymphocytosis caused by a disorder selected from the group consisting of: a viral infection, a bacterial infection, a protozoal infection Or the state after the spleen is removed. In one embodiment, the viral infection in any of the preceding embodiments is selected from the group consisting of infectious mononucleotococcus, hepatitis, and cellular giant viruses. In one embodiment, the bacterial infection in any of the preceding embodiments is selected from the group consisting of pertussis, tuberculosis, and brucellosis.

In some embodiments, the hyperproliferative disorder is selected from the group consisting of myeloproliferative disease (MPD), myeloproliferative neoplasms, polycythemia vera (PV), Essential thrombocytemia (ET), primary myelofibrosis (PMF), bone marrow development Myelodysplastic syndrome, chronic myelogenous leukemia (BCR-ABL1-positive), chronic neutrophilic leukemia, chronic eosinophilic leukemia, or mast cells Hyperplasia (mastocytosis).

In some embodiments, the inflammatory, immune, or autoimmune disorder is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease Skin diseases such as dryness, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma and melanoma, ulcerative colitis, atopic dermatitis, Bunionitis, spondylarthritis, uveitis, Behcets disease, rheumatic polymyalgia, giant cell arteritis, sarcoma-like disease, Kawasaki disease, juvenile idiopathic arthritis, suppurative sweat gland Inflammation, Sjögren's syndrome, dry arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, lupus, and lupus nephritis.

In some embodiments, the inflammatory, immune, or autoimmune disorder is a disease associated with vasculogenesis or angiogenesis in a mammal, which may manifest as tumor angiogenesis, chronic inflammatory disease Such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as cognac, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, colloid Tumor, melanoma, Kaposi's sarcoma and ovaries, breasts, Lung, pancreas, prostate, colon and epidermoid cancer.

In some embodiments, the inflammatory, immune, or autoimmune disorder is treatment, prevention, and/or treatment of asthma. The "asthma" used in this case covers airway compression that is unrelated to the cause, including reactive airway disease. Common triggers for asthma include, but are not limited to, exposure to environmental irritants (eg, allergens), cold air, warm air, perfume, moist air, exercise or labor, and emotional stress. The present invention also provides methods of treating, preventing, and/or treating one or more symptoms associated with asthma. Examples of symptoms include, but are not limited to, severe cough, airway compression, and mucus production.

The efficacy of combinations of the compounds and compounds described herein in the treatment, prevention, and/or management of other specified diseases or disorders described herein can also be tested using various models known in the art. The efficacy of treating, preventing and/or treating asthma can be assessed using an egg-induced asthma model as described, for example, in Lee, et al. , J. Allergy Clin. Immunol. 2006, 118, 403-9. The efficacy of treating, preventing, and/or treating arthritis (e.g., rheumatoid or dry arthritis) can be described, for example, in Williams, et al. , Chem. Biol . 2010, 17, 123-34, WO 2009/ The autoimmune animal models in 088986, WO 2009/088880, and WO 2011/008302 were evaluated. The efficacy of treating, preventing, and/or treating dryness can be used in a mouse model of gene transfer or knockout with target mutations in the epidermis, vasculature, or immune cells, a mouse model due to spontaneous mutation, and humans. Immunodeficient mouse models of skin or immune cell xenograft transplantation are evaluated, all of which are described, for example, in Boehncke, et al. , Clinics in Dermatology , 2007, 25 , 596-605. The efficacy of treating, preventing, and/or treating a fibrotic or fibrotic condition can be described using, for example, a unilateral ureteral obstruction model of renal fibrosis in Chevalier, et al. , Kidney International 2009, 75, 1145-1152. to Moore, et al, Am.J.Physiol.Lung.Cell Mol.Physiol 2008 , 294, L152-L160 Bo of pulmonary fibrosis of bleomycin (bleomycin) induced model;... described in (e.g.) Chuang, et al. , Clin . Liver Dis. 2008, 12, 333-347 and Omenetti, et al. , Laboratory Investigation , 2007, 87, 499-514 (biliary duct-ligated model) of various liver/biliary fibers A denaturation model; or any of the myeloid fiber degeneration mouse models such as those described in Varicchio, et al. , Expert Rev. Hematol. 2009, 2, 315-334. The efficacy of treating, preventing and/or treating scleroderma can be described by, for example, Yamamoto, et al. , J. Invest. Dermatol . 1999, 112, 456-462 by bleomycin. A mouse model of local injection induction was repeated for evaluation. The efficacy of treating, preventing and/or treating dermatomyositis can be induced, for example, by immunization with rabbit myosin as described in Phyanagi, et al. , Arthritis & Rheumatism, 2009, 60(10), 3118-3127. The myositis mouse model was evaluated. The efficacy of treating, preventing and/or treating lupus can be described, for example, in Ghoreishi, et al. , Lupus , 2009, 19, 1029-1035; Ohl, et al. , J. Biomed. & Biotechnol. , Article ID 432595 (2011); Xia, et al. , Rheumatology , 2011, 50, 2187-2196; Pau, et al. , PLoS ONE, 2012, 7(5) , e36761; Mustafa et al., Toxicology , 2011, 90, 156 -168; Ichikawa et al., Arthritis & Rheumatism , 2012, 62(2) , 493-503; Rankin, et al. , J. Immunology, 2012, 188, 1656-1667 for evaluation of various animal models. The efficacy of treating, preventing, and/or treating Sjögren's syndrome can be assessed by, for example, various mouse models in Chiorini, et al. , J. Autoimmunity , 2009, 33, 190-196. .

The efficacy of combining the compounds and compounds described herein in the treatment, prevention, and/or management of a given disease or disorder can be tested by various models known in the art. For example, a model for determining the efficacy of pancreatic cancer treatment is described in Herreros-Villanueva, et al. , World J. Gastroenterol. 2012, 18, 1286-1294. A model for determining the efficacy of breast cancer treatment is described, for example, in Fantozzi, Breast Cancer Res. 2006, 8, 212. A model for determining the efficacy of ovarian cancer treatment is described in Mulany, et al. , Endocrinology 2012, 153, 1585-92; and Fong, et al. , J. Ovarian Res. 2009, 2, 12. A model for determining the efficacy of melanoma treatment is described, for example, in Damsky, et al. , Pigment Cell & Melanoma Res. 2010, 23, 853-859. A model for determining the efficacy of lung cancer treatment is described, for example, in Meuwissen, et al. , Genes & Development , 2005, 19, 643-664. Determination of the efficacy of lung cancer treatment is the model described in (e.g.) Kim, Clin.Exp.Otorhinolaryngol 2009, 2, 55-60;.. And Sano, Head Neck Oncol 2009, 1, 32. A model for determining the efficacy of colorectal cancer treatment includes the CT26 model described, for example, in Castle, et al. , BMC Genomics, 2013, 15, 190; Endo, et al. , Cancer Gene Therapy , 2002, 9, 142-148; Roth et al. , Adv. Immunol. 1994, 57, 281-351; Fearon, et al., Cancer Res. 1988, 48, 2975-2980.

A model for determining the therapeutic efficacy of a blood malignant disease including B cell cancer can also be used. For example, the efficacy of diffuse large B-cell lymphoma (DLBCL) can be assessed using the PiBCL1 murine model and BALB/c (haplotype H-2d) mice. Illidge, et al. , Cancer Biother. & Radiopharm. 2000, 15, 571-80. The efficacy of non-Hodgkin's lymphoma (NHL) can be assessed in the 38C13 murine model of C3H/HeN (haplotype 2-Hk) mice or the 38C13 Her2/neu model. Timmerman, et al. , Blood 2001, 97, 1370-77; Penichet, et al. , Cancer Immunolog. Immunother. 2000, 49, 649-662. The potency of CLL can be assessed using the BCL1 model using BALB/c (haplotype H-2d) mice. Dutt, et al. , Blood , 2011, 117, 3230-29.

Instance

The implementation aspects covered in this case will now be illustrated by the following examples. The examples are provided for illustrative purposes only, and the disclosures of the present disclosure are in no way to be construed as limiting, and are intended to cover any and all variations that are apparent from the teachings provided. The reagents described in the examples are commercially available or can be prepared according to the procedures described in the literature.

Use the following abbreviations:

Example 1-General Synthesis of Quinazoline and Quinoline Derivatives

The quinazoline and quinoline derivatives included in the present invention can be obtained by a method known in the art of organic chemistry. See, for example, March, Advanced Organic Chemistry, 4th Edition, John Wiley & Sons, 2001. During the synthesis sequence, it may be necessary and/or desirable to protect any sensitive or reactive groups on the molecule. This is achieved by conventional protecting groups such as those described in T. W. Greene and P. G. M. Wutts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999. The protective substrate is optionally removed at a convenient subsequent stage using methods well known in the art.

If necessary, the reaction product is optionally isolated and purified using conventional techniques (but not limited to) by filtration, distillation, crystallization, chromatography, and the like. This material is optionally characterized using conventional methods including physical constants and measurements of spectral data.

The quinazoline and quinoline derivatives of formula I can be prepared by the general synthetic route shown in Figures 1-10.

Also included within the scope of the invention are all stereoisomeric forms of the quinazoline and quinoline derivatives according to the invention, for example, due to configuration or geometric isomerism. Such stereoisomeric forms include mirror image isomers, non-image isomers, cis and trans isomers, and the like. For example when using 4-( When morpholin-4-yl)pent-2-ynoic acid is used as the carboxylic acid, a mixture of two mirror image isomers is present. With respect to individual stereoisomers of a compound of formula I or a salt or solvate thereof, the invention includes the above stereoisomers which are substantially free, i.e. contain less than 5%, preferably less than 2% and especially less than 1 % other stereoisomers. Mixtures of stereoisomers in any ratio, for example, racemic mixtures comprising substantially equal amounts of the two mirror image isomers are also included within the scope of the invention.

In the case of chiral compounds, asymmetric synthesis methods for obtaining pure stereoisomers are known in the art, such as synthesis by chiral induction, synthesis by chiral intermediates, mirror-selective enzyme conversion, The stereoisomers are separated by chromatography on a chiral medium. Such methods are described in Collins, et al. , eds., Chirality in Industry , John Wiley & Sons, 1992. Similarly, methods for synthesizing geometric isomers are also well known in the art.

The quinazolines and quinoline derivatives of the invention, which may be in the form of the free base, may be separated from the reaction mixture in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts can also be obtained by using the free base of formula I as an organic or inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, It is obtained by treating methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.

The quinazoline and quinoline derivatives of the present invention are also present in an amorphous form. Multiple crystal forms (also known as polymorphs) are also possible. All physical forms are included within the scope of the invention.

The preparation of solvates is generally known. Thus, for example, Caira, et al. , J. Pharm. Sci. , 2004, 93 , 601-611 illustrate the preparation of the antifungal fluconazole in ethyl acetate and from solvates derived from water. Preparations of similar solvates, hydrates, and the like are described in van Tonder, et al. , AAPS PharmSciTech . , 2004, 5(1), article 12; and Bingham, et al. , Chem. Commun. 2001, 603- 604. A typical, non-limiting method involves dissolving the compound of the invention in a desired amount of the desired solvent above ambient temperature, cooling the solution at a rate sufficient to form crystallization, and then separating the crystals by standard methods. Analytical techniques such as IR spectroscopy show that the solvent (or water) is present in the crystallization as a solvate (or hydrate) form.

The invention also encompasses isotopically labeled compounds of the invention which are the same as those cited herein, but in fact one or more atoms are atomically possessed by atoms having an atomic mass or mass number different from those generally found in nature. Alternative. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, respectively. , ¹⁸ F, ³² P, ³⁵ S, and ³⁶ Cl.

Certain isotopically-labeled compounds of formula I (e.g., those labeled with ³ H and ¹⁴ C) can be used in compound and/or matrix tissue distribution assays. The cesium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred because of their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (ie, ² H) may result in certain therapeutic advantages due to greater metabolic stability (eg, increased in the half-life of the body or reduced dose requirements), so in some cases May be better. Isotopically labeled compounds of formula I can generally be prepared by substituting a suitable isotopically labeled reagent for a non-isotopically labeled reagent, following procedures similar to those disclosed in the Reaction Schemes and/or Examples below.

Example 2 - Analysis Method

The following liquid chromatography (LC) and mass spectrometry (MS) methods can be used to characterize the compounds encompassed by the present invention.

Method A

LC-MS spectrometer (Agilent)

Detector: DAD (210, 254 and 280 nm)

Quality Detector: API-ES (10-2000 amu, positive/negative ion mode)

Eluent (mobile phase): A: 0.1% formic acid MilliQ-water, B: acetonitrile

Column: Waters XTerra C18 MS, 50x4.6 mm ID, 2.5 μm

Flow rate: 0.5 ml / min

Gradient elution plan: 10.0 90 10

Method B

LC-MS Spectrometer (Waters); Detector: DAD (214 nm)

Quality Detector: API-ES (100-1000 amu, positive/negative ion mode)

Eluent (mobile phase): A: 0.1% trifluoroacetic acid (TFA) aqueous solution; B: acetonitrile

LC-MS flow method: gradient

Column: Acquity HSS-T3 (2.1 x 100 mm x 1.8 μm)

Flow rate: 0.3 ml / min

Gradient elution plan:

Method C

HPLC: Gilson Analytical HPLC System

Column: Phenomenex Luna C18(2) (100 x 2.00 mm, 5 μm)

Detector: UV/Vis (210/240nm)

Flow rate: 1 ml / min

Eluent (mobile phase): A: acetonitrile, B: acetonitrile / MilliQ - water = 1 / 9 (v / v), C: 0, 1% trifluoroacetic acid MilliQ - aqueous solution.

Gradient elution plan:

Method D

HPLC: Waters analytical HPLC system; column: SunFire-C18 (46 x 50 mm, 5 microns),

Detector: UV/Vis (210/240 nm), flow rate: 1 ml/min.

Eluent (mobile phase): A: 5 mM ammonium acetate solution, B: acetonitrile

Gradient elution plan:

Method E

HPLC: Waters analytical HPLC system; column: X-Bridge Shield-RP-18 (46 x 250 mm, 5 microns),

Detector: UV/Vis (210/240 nm), flow rate: 1 ml/min.

E eluent (mobile phase): A: 5 mM ammonium acetate in water, B: acetonitrile.

Gradient elution plan:

Example 3-4 Preparation of hydroxy- N- (pyridin-2-yl)benzamide (I-1)

The at 0 ℃ Me ₃ Al (2.0M in toluene of 60.4 mL, 121 mmol, 2.35 eq.) Was added to a stirred solution of methyl 4-hydroxybenzoate (7.35 g, 48.3 mmol, 1.0 eq.), 2-Aminopyridine (6.0 g, 48.3 mmol, 1.0 eq.) in tetrahydrofuran (60 mL). The reaction mixture was heated at 80 °C for 4 hours. After completion of the reaction (monitored by TLC), the reaction mixture was poured into a saturated aqueous saturated ammonium chloride solution. After stirring for 15 minutes, the mixture was extracted with 10% MeOH EtOAc. The crude product was recrystallized from hot ethyl acetate to afford purified 4-hydroxy-N-(pyridin-2-yl)benzamide (I-1) (9.2 g, 89%). ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm) = 8.36 (dd, 1H, J = 1.0,4.8Hz), 8.16 (d, 1H, J = 8.4Hz), 7.93 (d, 2H , J = 8.7 Hz), 7.80 (t, 1H, J = 5.7 Hz), 7.12 (dd, 1H, J = 1.0, 5.7 Hz), 6.83 (d, 2H, J = 8.7 Hz)

The following compounds were prepared in a similar manner to the one used for the preparation of I-1: 4-hydroxy- N- (4-methoxypyridin-2-yl)benzamide (I-2); 4-hydroxy-N -(4-Methylpyridin-2-yl)benzamide (I-3).

Example 4 Preparation of 4-Hydroxy- N- (4-ethylpyridin-2-yl)benzamide (I-4)

Preparation of 4-benzyloxybenzimid chloride. Add chloroform (6.5 ml, 75.6 mmol, 1.5 eq.) to a suspension of 4-benzyloxybenzoic acid (11.5 g, 50.4 mmol) followed by N,N-dimethylformamidine Amine (0.3 ml, catalytic amount) was added. Gas formation was observed and the mixture was stirred at room temperature for 2 hours during which time it became homogeneous. The volatile compound was removed under reduced pressure (45 ° C), and the residue was evaporated toluene to give a pale pink solid (13.4 g, quantitative).

4- (benzyloxy) - N - (4-ethyl-pyridin-2-yl) amine of the benzoyl. 4-Benzyloxybenzimid chloride (3.24 g, 13 mmol, 1 eq.) was added in portions to 2-amino-4-ethylaniline (2.4 g, 19.5 mmol, 1.5 eq.). The mixture was stirred at room temperature for 18 hours. Water was added to promote precipitation of the white solid, which was filtered and washed with water. The title compound was obtained as a white solid, which was used directly in the next step without further purification (3.7 g, 86%).

Preparation of benzoyl amine (4-ethyl-pyridin-2-yl) - 4-hydroxy - N. Palladium / carbon (370 mg, 10 wt%) was added to 4- (benzyloxy) - N - (4- pyridin-2-yl-ethyl) benzoyl-amine (3.7 g, 11.1 mmol, 1 eq. And a solution of ammonium formate (10.5 g, 167 mmol, 15 equivalents) in ethanol/water (1:1, 60 ml), and the resulting heterogeneous mixture was stirred at 90 ° C (external) for 2 hours. The mixture was filtered on celite, and the residue was washed ethyl acetate and ethyl acetate. The filtrate was evaporated under reduced pressure (50 ° C) and the crude compound was washed with water to remove residual NH ₄ HCO ₂ . Recrystallization from methanol gave the title compound as a white solid (2.0 g, 74%). LC-MS (Method A) Rt: 5.00 min; m / z 243.1 (M + H) +.

The following compounds were prepared in a similar manner to the one used for the preparation of I-4: 4-hydroxy- N- (4-phenylpyridin-2-yl)benzamide (I-5).

Example 5 Preparation of 4-Hydroxy- N- (4-propylpyridin-2-yl)benzamide (I-6)

This compound is essentially prepared as described for the preparation of compound I-1. The starting material 4-propylpyridin-2-amine is obtained by subjecting 4-propylpyridine to sodium chitin amination with Chichibabin amination.

Preparation of 4-propylpyridin-2-amine. Sodium azide (NaNH ₂ , 3.2 g, 82.5 mmol, 1.0 eq.) was pulverized to a fine powder and added to 4-propyl-pyridine (6) (10.0 g, 82.5 mmol) of isopropylidene In a solution of toluene (100 ml). The suspension was heated to 150-160 ° C under nitrogen. After about 30 minutes, the mixture began to darken until a full black mixture was obtained. Additional sodium amination was added at intervals of 1 hour (3 x 3.2 grams, 3.0 equivalents). After 6 hours, ¹ H NMR showed that 15% of the starting material remained, but the stepwise treatment was started anyway. The mixture was cooled to about 30 ° C and slowly poured into ice water (1 liter) with stirring. The aqueous phase was acidified with hydrochloric acid (6N, pH < 5), washed with dichloromethane (2×250 mL) and then basified with sodium hydroxide (33%, pH > The white suspension was extracted with EtOAc (3 mL EtOAc)EtOAc. By which on Silica (500 mL) was filtered (eluent: dichloromethane / methanol _{+ NH 4 (7N) .98:} 2 (2 liter) → 97:. 3 (2 liter)) were purified on. The purest fractions were combined and concentrated (vacuum, 45 ° C) to give the title compound as a brown oil (4.2 g, ~ 10% starting material). An additional material (1.4 g) was separated from the mixed fraction (total yield 50%).

Example 6 Preparation of 4-hydroxy- N- (4-ethynylpyridin-2-yl)benzamide (I-7)

Preparation of 4-((trimethyldecyl)ethyn-2-yl)pyridin-2-amine. 2-Amino-4-bromopyridine (380 mg, 2.2 mmol), hydrazine (triphenylphosphine) palladium (Pd(Ph ₃ ) ₄ , 213 mg, 0.18 mmol) and triethylamine (1.85 ml) A solution of 13 moles (6 eq.) in tetrahydrofuran (4 mL) was evaporated with nitrogen and then stirred under nitrogen for 40 min. Copper iodide (CuI, 100 mg; 0.53 mmol, 0.3 eq.) and (trimethyldecyl) acetylene (373 μL, 2.6 mmol, 1.2 eq.) were added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (EtOAc m. The residue was purified by EtOAc EtOAc (EtOAc)

Preparation of 4-[(4-((trimethyldecyl)ethyn-2-yl)pyridin-2-yl)aminocarboxamido]phenyl acetate. A solution of 4-acetoxybenzimidium chloride (1.3 g, 6.67 mmol, 1.0 eq.) in dichloromethane (8 mL) was slowly added to 4-((trimethyldecyl) acetylene-2- A solution of pyridin-2-amine (1.27 g, 6.67 mmol) in pyridine (10 mL). The reaction mixture was poured into water and extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The brown oil was taken in toluene and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc

Preparation of 4-hydroxy- N- (4-ethynylpyridin-2-yl)benzamide. 4-[(4-((Trimethyldecyl)ethyn-2-yl)pyridin-2-yl)aminocarboxylidene]phenyl ester (425 mg, 1.2 mmol) and potassium carbonate ( A 217 mg, 1.6 mmol, 1.3 eq. methanol (15 mL) suspension was stirred at room temperature for 1 hour. Hydrochloric acid (6N in water, 540 μL, 3.2 mmol, 2.7 eq.) was added, the vermiculite was added, and the mixture was concentrated. The solid was loaded onto a ruthenium dioxide column and purified by EtOAc (EtOAc (EtOAc) 76%). ¹ H NMR (400 MHz, CDCl ₃ , 300 K): δ (ppm) = 10.65 (1H, s), 10.20 (1H, br.s), 8.39 (1H, dd, J1 = 5.0 Hz, J2 = 0.8 Hz), 8.24 (1H, m), 7.93 (2H, d, J = 8.8 Hz), 7.20 (1H, dd, J1 = 5.0 Hz, J2 = 1.4 Hz), 6.82 (2H, d, J = 8.8 Hz), 4.61 ( 1H, s).

Preparation of (4-fluoro-2-yl) benzoyl amine (I-8) - A Example 7-4 - hydroxy - N

Preparation of 4-[(4-fluoropyridin-2-yl)aminomethylindenyl]phenyl acetate. A solution of 4-acetoxy benzamidine chloride (1.77 g, 8.92 mmol, 1.0 eq.) in dichloromethane (8 mL) was slowly added to 2-amino-4-fluoropyridine (1.0 g, 8.92) In a solution of pyridine (10 ml), the brown solution was stirred at room temperature overnight. The reaction mixture was concentrated to a small amount (to remove dichloromethane) and poured into water. The title compound (2.38 g, 97%) eluted elute LC-MS (Method A) Rt: 6.83 min; m / z 275.1 (M + H) +.

Preparation of N- (4-fluoropyridin-2-yl)-4-hydroxybenzamide. 4-[(4-Fluoropyridin-2-yl)aminocarbamido]phenyl acetate (2.38 g, 8.68 mmol) and potassium carbonate (1.56 g, 11.3 mmol, 1.3 equivalents) of methanol The (35 ml) suspension was stirred at room temperature for 1 hour. Hydrochloric acid (6N in water, 3.76 ml, 22.6 mmol, 2.7 eq.) was added (pH = ~ 7), the vermiculite was added, and the mixture was concentrated. The solid was supported on a ruthenium dioxide column and purified by EtOAc (EtOAc (EtOAc) %). LC-MS (Method A): Rt: 5.98 min; m / z 233.1 (M + H) +.

The following compounds were prepared using a procedure similar to that used for the preparation of I-8: 4-hydroxy- N- (4-trifluoromethylpyridin-2-yl)benzamide (I-9).

Preparation benzoyl amine (I-10) of (pyridin-2-yl) - Example 8-4-- [(6-amino-quinazolin-4-yl) oxy] - N

4 - [(6-nitro quinazolin-4-yl) oxy] - N - (pyridin-2-yl) amine of the benzoyl. 4-Chloro-6-nitroquinazoline (85 mg, 0.41 mmol), 4-hydroxy- N- (pyridin-2-yl)benzamide (95 mg, 0.44 mmol, 1.1 eq. And a suspension of potassium carbonate (61 mg, 0.44 mmol, 1.1 eq.) in acetonitrile (5 mL). The newly formed solid was filtered off and washed with acetonitrile. The residue was washed with dichloromethane through a filter, and then concentrated in vacuo, to yield 130 mg of a white solid 4 - [(6-nitro quinazolin-4-yl) oxy] - N - (pyridin - 2-yl)benzamide (82%). ¹ H NMR (400 MHz, CDCl ₃ , 300 K): δ (ppm) = 7.11 (1H, ddd, J1 = 7.3 Hz, J2 = 5.0 Hz, J3 = 1.0 Hz), 7.47 (2H, d, J = 8.8 Hz) , 7.80 (1H, m), 8.11 (2H, d, J = 8.8 Hz), 8.20 (1H, d, J = 9.2 Hz), 8.33 (1H, m), 8.40 (1H, dt, J1 = 8.4 Hz, J2 = 0.9 Hz), 8.64 (1H, s), 8.72 (1H, dd, J1 = 9.2 Hz, J2 = 2.3 Hz), 8.93 (1H, s), 9.33 (1H, dd, J1 = 2.8 Hz, J2 = 0.5Hz).

4 - [(6-amino-quinazolin-4-yl) oxy] - N - (pyridin-2-yl) amine of the benzoyl. Adding Raney nickel (ethanol suspension, 50 mg) to 4-[(6-aminoquinazolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide (53 mg) , a suspension of ethyl acetate/ethanol (2:1, 10 mL) of ammonium formate (100 mg, 1.5 mmol, 11 eq.), and the mixture was stirred at 30 ° C for 3 hours. The reaction mixture was filtered with EtOAc EtOAc. The residue was purified by ruthenium dioxide chromatography (0 to 40% of toluene) to give 16 mg of 4-[(6-aminoquinazolin-4-yl)oxy] - N -(pyridin-2-yl)benzamide (32%). ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm) = 5.99 (2H, s), 7.19 (1H, ddd, J1 = 7.3Hz, J2 = 4.9Hz, J3 = 0.9Hz), 7.24 ( 1H, d, J = 2.4 Hz), 7.39 (1H, dd, J1 = 9.0 Hz, J2 = 2.6 Hz), 7.45 (2H, d, J = 8.8 Hz), 7.71 (1H, d, J = 9.0 Hz) , 7.86 (1H, ddd, J1 = 9.3 Hz, J2 = 7.4 Hz, J3 = 1.9 Hz), 8.15 (2H, d, J = 8.8 Hz), 8.22 (1H, dt, J1 = 8.3 Hz, J2 = 0.9 Hz) ), 8.38 (1H, s), 841 (1H, ddd, J1 = 4.8 Hz, J2 = 1.9 Hz, J3 = 0.9 Hz), 10.88 (1H, s).

Preparation of (pyridin-2-yl) benzoyl amine (E-1) - A Example 9-4-- {[6- (Bingxi Xi-ylamino) quinazolin-4-yl] oxy} - N

The Bing Xixi chloride (50% of the methylene chloride solution, 26 [mu] L, 0.16 mmol, 0.8 eq.) Was added to 4 - [(6-amino-quinazolin-4-yl) oxy] - N - ( Pyridin-2-yl)benzamide (I-10, 79 mg, 0.20 mmol) and diisopropylethylamine (83 μL, 0.50 mmol, 2.5 equivalents) of dichloromethane/NMP ( In a 6:1, 7 ml) solution, the solution was stirred for an additional hour. The reaction mixture was concentrated, water was added, and the mixture was centrifuged. The supernatant was removed, and the solid was washed with water, methylene chloride / methanol (1:1), dried over sodium sulfate and evaporated. The residue was purified by ruthenium dioxide chromatography (0 to 8% methanol in dichloromethane) to give 36 mg of 4-{[6-(propenylamino) quinazolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl-amine (55%). LC-MS (Method A) Rt: 5.99 min; m / z 412.1 (M + H) + 1 H NMR (400MHz, DMSO-D 6, 300K):. Δ (ppm) = 5.86 (1H, dd, J1 = 10.0Hz, J2=1.9Hz), 6.35 (1H, dd, J1=16.9Hz, J2=1.9Hz), 6.52 (1H, dd, J1=16.9Hz, J2=10.0Hz), 7.19 (1H, ddd, J1) = 7.3 Hz, J2 = 4.8 Hz, J3 = 0.9 Hz), 7.51 (2H, d, J = 8.8 Hz), 7.87 (1H, m), 8.02 (1H, d, J = 9.0 Hz), 8.15 (1H, Dd, J1 = 9.2 Hz, J2 = 2.4 Hz), 8.17 (2H, d, J = 8.8 Hz), 8.22 (1H, d, J = 8.3 Hz), 8.41 (1H, m), 8.67 (1H, s) , 8.93 (1H, d, J = 2.3 Hz), 10.73 (1H, s), 10.91 (1H, s).

Example 10-4-{[6-(but-2-ynylamino) quinazolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide (E-2) Preparation

The diisopropylethylamine (70 [mu] L, 0.42 mmol, 3.5 eq.) Was added to 4 - [(6-amino-quinazolin-4-yl) oxy] - N - (pyridin-2-yl Benzoguanamine (I-10, 116 mg, 0.32 mmol), 2-butynoic acid (10 mg, 0.12 mmol, 1.0 eq.) and HATU (54 mg, 0.14 mmol, 1.2 eq.) In a solution of methyl chloride / NMP (3:1, 6 mL), the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, water was added, and the suspension was centrifuged. The supernatant was removed and the solid was rinsed with water. The residue was taken up in ethanol and concentrated. The residue was purified by the following preparative HPLC method: LUNA C18 column, 150 x 21.20 mm, 5 micron particle size, mobile phase 0 to 100% acetonitrile in water + trifluoroacetic acid, ie 26 mg white solid 4 - {[6- (but-2-yn-acyl amino) quinazolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl-amine trifluoroacetate (45%) . Other salts or free bases of E-2 can be prepared by standard methods. LC-MS (Method A) Rt: 6.30 min; m / z 424.1 (M + H) + 1 H NMR (400MHz, DMSO-D 6, 300K):. Δ (ppm) = 2.10 (3H, s), 7.20 (1H, ddd, J1 = 7.3 Hz, J2 = 4.8 Hz, J3 = 0.9 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.87 (1H, m), 8.00 (1H, d, J = 9.2 Hz) ), 8.07 (1H, dd, J1 = 9.1 Hz, J2 = 2.3 Hz), 8.17 (2H, d, J = 8.8 Hz), 8.22 (1H, dt, J1 = 8.4 Hz, J2 = 0.9 Hz), 8.41 ( 1H, d, J = 4.7 Hz), 8.67 (1H, s), 8.83 (1H, d, J = 2.3 Hz), 10.92 (1H, s), 11.20 (1H, s).

Example 11-4-- [(6-amino-quinazolin-4-yl) oxy] - N - [4- (trifluoromethyl) pyridin-2-yl] benzoyl-amine (I-11) The preparation

Of 4 - [(6-nitro quinazolin-4-yl) oxy] - N - [4- (trifluoromethyl) pyridin-2-yl] benzoyl preparation of amines. Cesium carbonate (480 mg, 2.8 mmol, 2 eq.) was added to a solution of 1-9 (400 mg, 1.4 m. 4-Chloro-6-nitroquinazoline (295 mg, 1.4 mmol, 1 eq.) was added and the mixture was stirred at 50 ° C for 6 hr. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (0 to 100%EtOAcEtOAcEtOAc) oxy] - N - [4- (trifluoromethyl) pyridin-2-yl] benzoyl-amine (21%).

4 - [(6-amino-quinazolin-4-yl) oxy] - N - [4- (trifluoromethyl) pyridin-2-yl] benzoyl preparation of amines. The Raney nickel was (suspension in ethanol, from about 100 mg) was added to 4 - [(6-nitro quinazolin-4-yl) oxy] - N - [4- (trifluoromethyl) pyridin-2 A solution of benzamidine (26 mg, 0.06 mmol) in ethyl acetate / ethanol (2:1, 20 mL). The reaction mixture was filtered, concentrated and purified eluted elut Extract with 2N sodium hydroxide, water and brine. The organic extract was dried over sodium sulfate and concentrated. The residue was purified by cerium oxide chromatography (0 to 40% toluene) to give 5 mg of 4-[(6-aminoquinazolin-4-yl)oxy] N- [4-(Trifluoromethyl)pyridin-2-yl]benzamide (20%). LC-MS (Method A) Rt: 7.38 min; m / z 426.0 (M + H) +.

Examples 12-4-- {[6- (Bingxi Xi-ylamino) quinazolin-4-yl] oxy} - N - [4- (trifluoromethyl) pyridin-2-yl] benzoyl amine ( Preparation of E-3)

This compound was obtained from the title compound (37 mg, 86%). LC-MS (method A) Rt: 7.86 min; m/z 480.0 (M+H) +. ¹ H NMR (400 MHz, CDCl ₃ , 300K): δ (ppm) = 5.89 (1H, dd, J1 = 10.2 Hz , J2 = 1.1 Hz), 6.35 (1H, dd, J1 = 16.8 Hz, J2 = 10.2 Hz), 6.55 (1H, dd, J1 = 16.8 Hz, J2 = 1.1 Hz), 7.32 (1H, d, J = 5.1) Hz), 7.45 (2H, d, J = 8.9 Hz), 7.67 (1H, s), 7.96 (1H, dd, J1 = 9.1 Hz, J2 = 2.4 Hz), 8.02 (1H, d, J = 9.0 Hz) , 8.07 (2H, d, J = 8.9 Hz), 8.49 (1H, d, J = 5.1 Hz), 8.71 (1H, s), 8.73 (1H, s), 8.75 (1H, s), 8.86 (1H, d, J = 2.1 Hz).

Examples 13-4-- {[6- (2-butyn-acyl amino) quinazolin-4-yl] oxy} - N - (4- trifluoromethyl-pyridin-2-yl) benzoyl Preparation of amine (E-4)

This was obtained from the title compound (10 mg, 21%). ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm) = 2.10 (3H, s), 7.52 (2H, d, J = 8.8Hz), 7.55 (1H, d, J = 5.3Hz), 8.00 (1H, d, J = 9.1 Hz), 8.07 (1H, dd, J1 = 9.0 Hz, J2 = 2.4 Hz), 8.19 (2H, d, J = 8.8 Hz), 8.57 (1H, s), 8.67 ( 1H, s), 8.69 (1H, d, J = 5.4 Hz), 8.83 (1H, d, J = 2.3 Hz).

Preparation benzoyl amine (I-12) of (pyridin-2-yl) - Example 14-4-- [(6-amino-quinazolin-4-yl) amino] - N

Preparation of N' -(2-cyano-4-nitrophenyl) -N,N -dimethyliminocarbamidine. 5-Nitro-aminobenzonitrile (5.0 g, 36.5 mmol) and dimethylformamide dimethyl acetal (20 mL) were refluxed for 2 h. The resulting mixture was cooled and filtered. The solid was washed with several portions of diethyl ether and dried in vacuo to give 6.45 g of N --(2-cyano-4-nitrophenyl) -N,N -dimethylimine as a yellow solid. Base carbamide (81%).

4 - [(6-nitro quinazolin-4-yl) amino] - N - (pyridin-2-yl) amine of the benzoyl. Add N '-(2-cyano-4-nitrophenyl)-N,N-dimethyliminocarbamidine (1.37 g, 6.3 mmol, 1.0 eq.) to 4-amino- A suspension of N- (2-pyridyl)benzamide (1.34 g, 6.3 mmol) in acetic acid (25 mL). After the reaction was cooled to room temperature, the formed precipitate was filtered and washed with diethyl ether to give 692 g of 4-[(6-nitroquinazolin-4-yl)amino]-N as a yellow solid. -(pyridin-2-yl)benzamide (25%).

4 - [(6-amino-quinazolin-4-yl) amino] - N - (pyridin-2-yl) amine of the benzoyl. Iron powder (450 mg, 8.1 mmol, 7 eq.) Was added to 4 - [(6-nitro quinazolin-4-yl) amino] - N - (pyridin-2-yl) benzoyl amine (520 mg, 1.14 mmol) and acetic acid (335 μL, 5.7 mmol, 5 eq.) in tetrahydrofuran (25 mL), and the mixture was refluxed for 2 hr. The reaction mixture was diluted with ethyl acetate and poured into EtOAc (~~~~~~~~ The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silicon dioxide (0 to 80% acetone in toluene) were purified, to obtain 270 mg of 4 - [(6-amino-quinazolin-4-yl) amino] - N - ( Pyridin-2-yl)benzamide (67%).

Preparation of (pyridin-2-yl) benzoyl amine (E-5) - A Example 15-4-- {[6- (Bingxi Xi-ylamino) quinazolin-4-yl] amino} - N

The title compound (15 mg, 18%) was obtained from m. ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm) = 5.86 (1H, dd, J1 = 10.2Hz, J2 = 1.9Hz), 6.36 (1H, dd, J1 = 16.9Hz, J2 = 1.9 Hz), 6.54 (1H, dd, J1 = 16.9 Hz, J2 = 10.2 Hz), 7.17 (1H, ddd, J1 = 7.3 Hz, J2 = 4.8 Hz, J3 = 0.9 Hz), 7.85 (2H, m), 7.95 (1H, dd, J1 = 9.0 Hz, J2 = 2.1 Hz), 8.04 (2H, m), 8.10 (2H, m), 8.22 (1H, dt, J1 = 8.3 Hz, J2 = 0.9 Hz), 8.40 (1H) ,ddd,J1=4.8Hz, J2=2.0Hz, J3=0.8Hz), 8.64(1H,s),8.87(1H,d,J=1.9Hz),10.09 (1H,s),10.55(1H,s ), 10.68 (1H, s).

Examples 16-4-- {[6- (but-2-yn-acyl amino) quinazolin-4-yl] amino} - N - (pyridin-2-yl) benzoyl amine (E-6) Preparation

This compound was prepared from the compound I-12 and 2-butynoic acid in a manner similar to that described for the preparation of compound E-2. The title compound (28 mg, 21%) was obtained eluted eluted eluted elute ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm) = 2.10 (3H, s), 7.17 (1H, ddd, J1 = 7.3Hz, J2 = 4.8Hz, J3 = 1.0Hz), 7.83 ( 3H, m), 8.00 (2H, d, J = 8.8 Hz), 8.09 (2H, d, J = 8.8 Hz), 8.22 (1H, dt, J1 = 8.3 Hz, J2 = 0.8 Hz), 8.40 (1H, m), 8.63 (1H, s), 8.80 (1H, s), 10.07 (1H, s), 10.68 (1H, s), 10.99 (1H, s).

Preparation benzoyl amine (I-13) of (pyridin-2-yl) - Example 17-4-- [(6-amino-7-methoxy-quinazolin-4-yl) oxy] - N

4 - [(7-methoxy-6-nitro quinazolin-4-yl) oxy] - N - (pyridin-2-yl) amine of the benzoyl. Add 4-chloro-7-methoxy-6-nitroquinazoline (201 mg, 0.84 mmol) in acetonitrile (15 mL) to 4-hydroxy- N- (pyridin-2-yl)benzene To a mixture of methotrexate (215 mg, 1.01 mmol, 1.2 eq.) and potassium carbonate (174 mg, 1.26 mmol, 1.5 eq.), the suspension was heated in a microwave oven at 150 ° C for one hour. The reaction mixture was diluted with water, filtered and washed with water. The solid was co-evaporated twice with toluene to give 162 mg of 4-[(7-methoxy-6-nitroquinazolin-4-yl)oxy] -N- (pyridine- 2-yl)benzamide (46%). LC-MS (Method A) Rt: 7.28 min; m / z 418.1 (M + H) +.

4 - [(6-amino-7-methoxy-quinazolin-4-yl) oxy] - N - (pyridin-2-yl) amine of the benzoyl. 4 - [(7-methoxy-6-nitro quinazolin-4-yl) oxy] - N - (pyridin-2-yl) benzoyl-amine (80 mg, 0.19 mmol) and A mixture of ethyl acetate/ethanol (4:1, 10 ml) of Resin nickel (about 100 mg, ethanol suspension) was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered on a 4 micron HPLC filter and the filtrate was concentrated. The residue was purified by cerium oxide chromatography (0 to 40% of toluene) to give 35 mg of yellow solid 4-[(6-amino-7-methoxyquinazoline-4) - yl) oxy] - N - (pyridin-2-yl) benzoyl-amine (48%). LC-MS (Method A) Rt: 5.84 min; m / z 388.2 (M + H) +.

Examples 18-4-- {[6- (Bingxi Xi-ylamino) -7-methoxy-quinazolin-4-yl] amino} - N - (pyridin-2-yl) benzoyl amine (E- 7) Preparation

This was obtained from the title compound (11 mg, 22%). LC-MS (method A) Rt: 6.42 min; m/z 442.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-D ₆ , 300K): δ (ppm) = 4.11 (3H, s), 5.82 (1H, dd, J1 = 10.1 Hz, J2 = 1.8 Hz), 6.33 (1H, dd, J1 = 16.9 Hz, J2 = 1.8 Hz), 6.87 (1H, dd, J1 = 16.9 Hz, J2 = 10.2 Hz), 7.21 (1H, ddd, J1 = 7.3 Hz, J2 = 4.9 Hz, J3 = 1.0 Hz), 7.49 (3H, m), 7.89 (1H, m), 8.17 (2H, d, J = 8.9 Hz), 8.21 ( 1H, dt, J1 = 8.4 Hz, J2 = 0.9 Hz), 8.42 (1H, m), 8.63 (1H, s), 9.21 (1H, s), 9.88 (1H, s) 10.96 (1H, s).

Examples 19-4-- {[6- (acyl-2-ynyl) -7-methoxy-quinazolin-4-yl] amino} - N - (pyridin-2-yl) benzoyl Preparation of amine (E-8)

This compound was obtained from the title compound (2 mg, 5%). LC-MS (Method A) Rt: 6.72 min; m / z 454.2 (M + H) +.

Example 20-4-- [(6-amino-7-methoxy-quinazolin-4-yl) oxy] - N - (4- (trifluoromethyl) pyridin-2-yl) benzoyl amine Preparation of (I-14)

This compound is prepared in substantially the same manner as in the preparation of compound I-13, using compound I-9 and 4-chloro-7-methoxy-6-nitroquinazoline as starting materials. (15 mg, 82%). LC-MS (Method A) Rt: 7.48 min; m / z 456.1 (M + H) +.

Examples 21-4-- {[6- (Bingxi Xi-ylamino) -7-methoxy-quinazolin-4-yl] amino} - N - (4- (trifluoromethyl) pyridin-2-yl Preparation of benzoguanamine (E-9)

This was obtained from the title compound (11 mg, 22%). LC-MS (Method A) Rt: 8.08 min; m / z 510.1 (M + H) + 1 H NMR (400MHz, CDCl 3, 300K):. Δ (ppm) = 4.13 (3H, s), 5.87 (1H , dd, J1 = 10.1 Hz, J2 = 1.2 Hz), 6.37 (1H, dd, J1 = 16.8 Hz, J2 = 10.1 Hz), 6.53 (1H, dd, J1 = 16.8 Hz, J2 = 1.2 Hz), 7.31 ( 1H, m), 7.38 (1H, s), 7.44 (2H, d, J = 8.8 Hz), 8.07 (2H, d, J = 8.8 Hz), 8.20 (1H, s), 8.49 (1H, d, J =5.1 Hz), 8.67 (1H, s), 8.72 (1H, s), 8.77 (1H, s), 9.43 (1H, s).

Examples 22-4-- {[6- (acyl-2-ynyl) -7-methoxy-quinazolin-4-yl] amino} - N - (4- (trifluoromethyl) pyridine Preparation of -2-yl)benzamide (E-10)

Add oxaloquinone chloride (10 μl, 0.119 mmol) to +1 drop of N,N-dimethylformamide (N,N-dimethylformamide) to 2-butynoic acid (10 mg, 0.119 mmol of acetonitrile (800 μl) in solution. The reaction mixture was stirred at 50 ° C for 30 minutes and then cooled to room temperature. A solution of the compound I-14 (15 mg, 0.033 mmol) in methylene chloride / NMP (5:1, 4 mL) was cooled in an ice bath and then a solution of decyl chloride (0.119 mmol, 2 eq) Join. After 5 hours, the dichloromethane was removed in vacuo and the residue was taken water. Collect solids, wash with water, and then with The alkane co-evaporates. The residue was purified by preparative HPLC using the following procedure: column: LUNA C18, 150 x 21.20 mm, 5 micron particle size, mobile phase: 0 to 100% acetonitrile in water + trifluoroacetic acid, titled white solid Compound (2 mg, 10%). LC-MS (Method A) Rt: 8.21 min; m / z 261.6 ((M + H) / 2) +.

Preparation benzoyl amine (I-15) of (2-pyridyl) - Example 23-4-- [(7-hydroxy-6-nitro-4-quinolyl) oxy] - N

Preparation of 3-isopropoxy-4-nitroaniline: Sodium metal (29.4 g, 1288 mmol, 5 eq.) was taken in isopropanol (IPA, 1600 mL) and refluxed to 100 °C. When all of the sodium metal was dissolved, the solution was cooled to room temperature and 3-fluoro-4-nitroaniline (40 g, 256 mmol, 1 equivalent) was added. The reaction mixture was heated at 60 °C for 16 hours. The reaction mixture was then evaporated and poured into ice cold water. The obtained solid was filtered, washed with cold water and then dried to give 3-isopropoxy-4-nitroaniline (47.5 g, 94%). _{^{1 H NMR (400MHz, CDCl 3}} , 300K): δ (ppm) = 7.75 (1H, d, J = 8.7Hz), 6.46 (2H, s), 6.27 (1H, s), 6.16 (1H, d, J =8.6 Hz), 4.57 (1H, s), 1.30 (6H, m)

5-(((3-isopropoxy-4-nitrophenyl)amino)methyl)2,2-dimethyl-1,3-di Preparation of alkane-4,6-dione: 2,2-dimethyl-1,3-di A solution of the alkyl-4,6-dione (Meldrum's acid, 52.33 g, 363 mmol, 1.5 eq.) in triethyl orthoformate (530 mL, 13 eq.) was heated at 105 °C for 2 h. 3-Isopropoxy-4-nitroaniline (47.5 g, 242 mmol, 1 eq.) was added and the mixture was stirred at 105 ° C overnight. After completion, the reaction mixture was cooled to room temperature and diluted with hexane. The precipitated solid was filtered off, washed with hexane and dried to give 5-(((3-isopropoxy-4-nitrophenyl)amino)methyl) ,2-dimethyl-1,3-di Alkane-4,6-dione (80 g, 95.2%). ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm) = 11.24 (1H, s), 8.69 (1H, s), 7.91 (1H, d, J = 8.8Hz), 7.66 (1H, s ), 7.26 (1H, d, J = 8.5 Hz), 4.91 (1H, m), 1.68 (6H, s), 1.32 (6H, m)

Preparation of 7-isopropoxy-6-nitroquinolin-4-ol: 5-(((3-isopropoxy-4-nitrophenyl)amino)methyl)2,2 -dimethyl-1,3-di A suspension of the alkane-4,6-dione (40 g, 114 mmol, 1 eq.) in diphenyl ether (400 mL) was heated at 200 ° C for one hour. After completion, the reaction mixture was cooled to room temperature and diluted with hexane. The obtained solid was filtered, washed with hexane and dried to give 7-isopropoxy-6-nitroquinolin-4-ol (27 g, 95%) as a brown solid. Go to the next step without purification.

Preparation of 4-chloro-7-isopropoxy-6-nitroquinoline: crude 7-isopropoxy-6-nitroquinolin-4-ol (27 g, 108.7 mmol, 1 equivalent A solution of phosphonium chloride (240 ml) and N,N-dimethylformamide (0.4 ml) was heated at 110 °C for 3 hours. After completion, the reaction mixture was concentrated, washed with aqueous sat. The organic extract was washed with brine, dried over sodium sulfate and evaporated to dryness Liquid 4-chloro-7-isopropoxy-6-nitroquinoline (11 g, 38%). ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm) = 8.91 (1H, d, J = 4.6Hz), 8.66 (1H, s), 7.98 (1H, s), 7.75 (1H, d , J = 4.4 Hz), 5.06 (m, 1H), 1.35 (m, 6H).

4 - ((7-isopropyl-6-nitro-quinolin-4-yl) oxy) - N - benzoyl Preparation of amine (pyridin-2-yl): The three-butoxide (9.1克, 81 mmol, 2.2 eq.) to 4-chloro-7-isopropoxy-6-nitroquinoline (10 g, 37 mmol, 1 eq.) and compound I-1 (9.52 g, 44 mmol, 1.2 eq.) in N,N-dimethylformamide (100 mL). The reaction mixture was heated at 120 °C for 30 minutes. Upon completion, the reaction mixture was poured into ice water. The resulting solid was filtered off and redissolved in dichloromethane. The methylene chloride layer was washed with brine, dried over sodium sulfate and concentrated to give a crude compound, which was purified by flash column chromatography (4% methanol in dichloromethane). brown solid form of 4 - ((7-isopropyl-6-nitro-quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzoyl-amine (13 g, 78%) . ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm) = 10.89 (s, 1H), 8.80 (d, 1H, d, J = 5.1Hz), 8.75 (1H, s), 8.40 (d , 1H, J = 4.04 Hz), 8.20 (d, 3H, J = 8.4 Hz), 7.86 (m, 1H), 7.79 (s, 1H), 7.45 (d, 2H, J = 8.5 Hz), 7.18 (m) , 1H), 6.71 (d, 1H, J = 5.1 Hz), 5.06 (m, 1H), 1.36 (m, 6H)

4 - ((7-hydroxy-6-nitro-quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzoyl amine. At 0 ℃ aluminum trichloride (18 g, 134 mmol, 5 eq) was added to 4 - ((7-isopropyl-6-nitro-quinolin-4-yl) oxy) - N - (Pyridine-2-yl)benzamide (12 g, 26 mmol, 1 eq.) in dichloromethane (300 mL). The reaction mixture was stirred vigorously for 2 hours to reach room temperature. After completion, the reaction mixture including the solid was poured into 1N sodium hydroxide and stirred for another 10 minutes. The mixture was acidified with solid citric acid and extracted with ethyl acetate: tetrahydrofuran (3:1). The aqueous layer was basified to pH ~ 8 with solid sodium hydrogen carbonate and extracted with ethyl acetate: tetrahydrofuran (3:1). The combined organic layer was dried over sodium sulfate and concentrated to give a crude product which was purified by EtOAc EtOAc EtOAc 7-hydroxy-6-nitro-quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzoyl-amine (10 g, 92%). ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm) = 11.63 (bs, 1H), 10.88 (s, 1H), 8.75 (m, 2H), 8.40 (d, 1H, J = 3.8Hz ), 8.20 (d, 3H, J = 8.7 Hz), 7.85 (m, 1H), 7.56 (s, 1H), 7.45 (d, 2H, J = 8.6 Hz), 7.17 (m, 1H), 6.63 (d) , 1H, J = 5.2Hz).

Example 24-4-[[6-Amino-7-(2- Preparation benzoyl amine (I-16) of (2-pyridyl) - morpholino ethoxy) -4-quinolyl] oxy] - N

4-[[7-(2- Morpholino ethoxy) -6-nitro-4-quinolyl] oxy] - N - (2- pyridin-benzoyl Preparation of amine) group. Potassium carbonate (777 mg, 5.7 mmol, 2.3 equivalents), 4-(2-chloroethyl)- Phytate hydrochloride (508 mg, 2.73 mmol, 1.1 equivalents) and sodium iodide (catalytic amount) added to compound I-15 (1.0 g, 2.48 mmol) of N,N-dimethylformamide (70 ml) in a solution, the dark red mixture was stirred at 50 ° C overnight. The reaction mixture was acidified to pH = 5 with citric acid, saturated sodium bicarbonate (aqueous) was added and the mixture was filtered. The residue was purified by cerium oxide chromatography (0 to 15% methanol in ethyl acetate) to give 4-[[--[2- Oxoethoxyethoxy)-6-nitro-4-quinolinyl]oxy]-N-(2-pyridyl)benzamide (905 mg, 71%). LC-MS (Method A) Rt: 4.19 min; m / z 516.1 (M + H) + 1 H NMR (400MHz, DMSO-D 6, 300K):. Δ (ppm) = 2.52 (4H, m), 2.79 (2H, t, J = 5.4 Hz), 3.58 (4H, t, J = 4.6 Hz), 4.45 (2H, t, J = 5.3 Hz), 6.73 (1H, d, J = 5.3 Hz), 7.19 (1H) ,ddd,J1=7.3Hz, J2=4.8Hz, J3=1.0Hz), 7.47(2H,d,J=8.9Hz),7.82(1H,s),7.86(1H,m),8.21(3H,m ), 8.41 (1H, ddd, J1 = 4.8 Hz, J2 = 2.0 Hz, J3 = 0.9 Hz), 8.80 (1H, s), 8.83 (1H, d, 5.3 Hz), 10.90 (1H, s).

4-[[6-Amino-7-(2- Morpholino ethoxy) -4-quinolyl] oxy] - N - (2- pyridyl) benzoyl preparation of amines. Add palladium/carbon (50% water, 10%, about 50 mg) to 4-[[7-(2- Morpholino ethoxy) -6-nitro-4-quinolyl] oxy] - N - (2- pyridyl) benzoyl-amine (130 mg, 0.25 mmol) of tetrahydrofuran / ethanol (2: In a solution of 1,25 ml), the reaction mixture was stirred at 50 ° C for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered over EtOAc (EtOAc) eluted elute Morpholino ethoxy) -4-quinolyl] oxy] - N - (2- pyridyl) benzoyl-amine (94 mg, 77%). LC-MS (Method A) Rt: 2.98 min; m / z 486.2 (M + H) +.

Example 25-4-[[7-(2-{ 4-yl} o-ethoxy) -6- (but-2-yn-acyl amino) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine ( Preparation of E-11)

EDCI.HCl (70 mg, 0.37 mmol, 2.5 equivalents) was added to compound E-9 (71 mg, 0.15 mmol), and 2-butynoic acid (24 mg, 0.29 mmol, 2.0 eq.) In a solution of pyridine (3 ml), the solution was stirred at room temperature for 2 hr. The reaction mixture was concentrated and co-evaporated twice with toluene. The residue was purified by preparative HPLC using a LUNA (C18) 150 x 21.20 mm 5 micron column and a mobile phase 0 to 80% aqueous acetonitrile + trifluoroacetic acid. The pure fractions were combined, diluted with tetrahydrofuran and washed with saturated sodium bicarbonate / saturated brine. The aqueous phase was extracted once with tetrahydrofuran. The combined organic extracts were washed with brine, dried over sodium sulfate The residue was triturated with EtOAc (EtOAc) LC-MS (Method A) Rt: 3.53 min; m / z 552.1 (M + H) +, HPLC ( Method C) Rt: 4.73 min ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm. ) = 2.07 (3H, s), 2.53 (4H, m), 2.83 (2H, t, J = 5.9 Hz), 3.62 (4H, t, J = 4.6 Hz), 4.38 (2H, t, J = 5.9 Hz) ), 6.67 (1H, d, J = 5.1 Hz), 7.18 (1H, ddd, J1 = 7.4 Hz, J2 = 4.8 Hz, J3 = 1.0 Hz), 7.36 (2H, d, J = 8.9 Hz), 7.60 ( 1H, s), 7.85 (1H, m), 8.19 (3H, m), 8.40 (1H, ddd, J1 = 4.8 Hz, J2 = 1.9 Hz, J3 = 0.8 Hz), 8.63 (1H, d, J = 5.2 Hz), 8.71 (1H, s), 9.71 (1H, s), 10.82 (1H, s).

Example 26-4-[[7-(2-{ 4-yl} o-ethoxy) -6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine (E-12) Preparation

Add EDCI.HCl (86.86 mg, 0.45 mmol) to a solution of compound I-16 (88 mg, 0.18 mmol) and acrylic acid (0.02 mL, 0.3600 mmol) in pyridine (3 mL) Stir at room temperature for 2 hours. The reaction mixture was concentrated, co-evaporated twice with toluene, and the residue was purified by preparative HPLC using a LUNA (C18) 150 x 21.20 mm 5 micron column and mobile phase 0 to 50% aqueous acetonitrile + trifluoroacetic acid. The fractions containing the desired product were taken up in tetrahydrofuran and washed with saturated aqueous sodium bicarbonate / saturated brine. The organic extract was dried over sodium sulfate and concentrated in vacuo. The residue was triturated with EtOAc (EtOAc) LC-MS (method A) Rt: 3.41 min; m/z 540.1 (M+H) ⁺ , HPLC (Method C) Rt: 4.49.

Example 27-4-- [[6-amino-7- (2-methoxyethoxy) -4-quinolyl] oxy] - N - (2- pyridyl) benzoyl amine (the I- 17) Preparation

Preparation of 3-(2-methoxyethoxy)-4-nitroaniline. Add sodium hydride (60% dispersion) (589.33 mg, 14.73 mmol) to a solution of 2-methoxyethanol (5 mL, 63.41 mmol) in tetrahydrofuran (15 mL). Stir for 1 hour. 3-Fluoro-4-nitro-phenylamine (1 g, 6.41 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated brine and extracted twice with THF. The combined organic extracts were dried <RTI ID=0.0> LC-MS (Method A) Rt: 3.82 min; m / z 213.1 (M + H) +.

5-({[3-(2-methoxyethoxy)-4-nitrophenyl]amino}methylene)-2,2-dimethyl-1,3-di Preparation of alkane-4,6-dione. 2,2-dimethyl-1,3-di A solution of the alkoxy-4,6-dione (0.92 g, 6.41 mmol) in diethoxymethoxyethane (1.07 mL, 6.41 mmol) was stirred at &lt 3-(2-Methoxyethoxy)-4-nitro-phenylamine (1.36 g, 6.41 mmol) was added and the mixture was stirred at 105 ° C overnight. The reaction mixture was cooled to room temperature, heptane (50 ml) was added, and the solid was filtered, washed with heptane and dried under vacuum to give a brown solid 5--[{[3-(2) -methoxyethoxy)-4-nitrophenyl]amino}methylene)-2,2-dimethyl-1,3-di Alkane-4,6-dione (2.05 g, 87%). This material was used directly in the next step.

Preparation of 7-(2-methoxyethoxy)-6-nitroquinoline-4(1 H )-one. 5-({[3-(2-methoxyethoxy)-4-nitrophenyl]amino}methylene)-2,2-dimethyl-1,3-di A solution of the alkane-4,6-dione (2.05 g, 5.6 mmol) in diphenyl ether (25 mL) was stirred at 200 ° C for one hour. The reaction mixture was cooled to room temperature and then heptane (25 mL). The solid was filtered off, washed with heptane and dried to give 7-(2-methoxyethoxy)-6-nitroquinolin-4( 1H )-one (0.95) as a brown solid. Gram, 64%). LC-MS (Method A) Rt: 3.46 min; m/z 265.0 (M+H) ⁺ . The following analytical methods can be used to characterize the compounds included in the present invention.

Preparation of 4-chloro-7-(2-methoxyethoxy)-6-nitroquinoline. Add N,N-dimethylformamide (0.1 mL, 1.3 mmol) to 7-(2-methoxyethoxy)-6-nitroquinolin-4(1 H )-one ( 0.95 g, 3.6 mmoles of a solution of phosphonium chloride (5 ml, 53.48 mmol), and the mixture was stirred at 105 ° C for 1 hour. The reaction mixture was concentrated, taken up in EtOAc EtOAc. The combined organic extracts were washed with saturated brine, dried over sodium sulfate The residue was purified by silica gel chromatography (0 to 100% ethyl acetateEtOAc) to give 4-chloro-7-(2-methoxyethoxy)-6 as a yellow solid. -Nitroquinoline (688 mg, 68%). LC-MS (method A) Rt: 5.72 min; m/z 283.1 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-D ₆ , 300K): δ (ppm) = 3.48 (3H, s), 3.86 (2H, t, J = 4.6 Hz), 4.40 (2H, t, J = 4.6 Hz), 7.48 (1H, d, J = 4.8 Hz), 7.65 (1H, s), 8.65 (1H, s), 8.83 (1H,d,J=4.8Hz)

4 - [(7- (2-methoxyethoxy) -6-nitro-quinolin-4-yl) oxy] - N - (pyridin-2-yl) amine of the benzoyl. Potassium tert-butoxide (229.44 mg, 2.04 mmol) was added to 4-hydroxy- N- (2-pyridyl)benzamide (283.43 mg, 1.32 mmol) and 4-chloro-7- ( a suspension of 2-methoxyethoxy)-6-nitro-quinoline (340 mg, 1.2 mmol) in tetrahydrofuran (14 mL) and NMP (3 mL). Heat at °C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed twice with 0.1N sodium hydroxide (aq.) and brine (EtOAc) The residue is purified by cerium oxide chromatography (0 to 80% acetone in toluene) to give 4-[(7-(2-methoxyethoxy)-6-nitro) as a yellow solid. Quinoline-4-yl)oxy]-N-(pyridin-2-yl)benzamide (303 mg, 55% yield). LC-MS (Method A) Rt: 5.34 min; m / z 461.1 (M + H) +.

4 - [[6-amino-7- (2-methoxyethoxy) -4-quinolyl] oxy] - N - (2- pyridyl) benzoyl preparation of amines. Palladium/carbon (containing 50% water, 10%, about 100 mg) was added to 4-[(7-(2-methoxyethoxy)-6-nitroquinolin-4-yl)oxy] - a solution of N- (pyridin-2-yl)benzamide (300 mg, 0.65 mmol) in tetrahydrofuran (25 ml) and ethanol (5 ml), and the mixture was stirred at 50 ° C under hydrogen atmosphere. 3 hours. The reaction mixture was filtered, washed with EtOAc (EtOAc) (EtOAc) oxy] - N - (2- pyridyl) benzoyl-amine (365 mg, 130% yield). LC-MS (Method A) Rt: 3.81 min; m / z 431.1 (M + H) +.

Example 28-4-- [[7- (2-methoxyethoxy) -6- (but-2-yn-acyl amino) quinolin-4-yl] oxy] - N - (pyridin-2 -base) Preparation of benzamide (E-13)

This was obtained from the title compound (17 mg, 19%). LC-MS (method A) Rt: 4.27 min; m/z 497.1 (M+H) ⁺ , HPLC (method C) Rt: 5.96.

Preparation of (pyridin-2-yl) benzoyl amine (I-18) - A Example 29-4-- {[6- (methylamino) quinolin-4-yl] oxy} - N

4 - {[6-nitro) quinolin-4-yl] oxy} - N - (pyridin-2-yl) amine of the benzoyl. Compound I-1 (108 mg, 0.50 mmol), 4-chloro-6-nitroquinoline (100 mg, 0.48 mmol) and potassium carbonate (83 mg; 0.60 mmol) of acetonitrile (1) The ml) suspension was stirred in a microwave oven at 150 ° C for 8 hours. The brown solid was filtered off and washed with acetonitrile and water. The product was purified using silica gel chromatography (dichloromethane/methanol = 95/5 v/v%) to give &lt;RTI ID=0.0&gt; N- (pyridin-2-yl)benzamide (69.3%). LC-MS (Method A) Rt: 7.31 min; m / z 387.1 (M + H) +.

4 - {[6- (methylamino) quinolin-4-yl] oxy} - N - (pyridin-2-yl) amine of the benzoyl. Palladium / carbon (50% aqueous moisture, catalytic amount) was added to 4 - {[6- (nitro) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine ( 70 mg, 0.18 mmol) in ethyl acetate (4 mL) and ethanol (4 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere overnight. Palladium/carbon was removed by filtration on dicalite. The filtrate was concentrated under reduced pressure, to obtain 53 mg of a brown solid form of 4 - {[6- (methylamino) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl Amine (82%). LC-MS (Method A) Rt: 4.65 min; m / z 357.2 (M + H) +.

Preparation benzoyl amine (E-14) of (pyridin-2-yl) - Example 30-4-- {[6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy} - N

Acetylhydrazine chloride (5.9 μL, 0.072 mmol) was added to a solution of compound I-18 (25 mg, 0.065 mmol) in tetrahydrofurane (2 mL). The resulting mixture was stirred at -10 °C for 10 minutes. Diisopropylethylamine (13.4 microliters, 0.081 millimoles) was added to the resulting suspension. The resulting solution was stirred at -10 °C for 30 minutes and at room temperature for 3 hours. The mixture was concentrated in vacuo. The product was purified using silica gel chromatography (dichloromethane/methanol = 9/1 v/v%) to give 11.4 mg of 4-{[6-((- phenyl)amino) quinolin-4-yl] yl} - N - (pyridin-2-yl) benzoyl amine. LC-MS (Method A) Rt: 5.12 min; m / z 411.2 (M + H) +.

Examples 31-4-- {[6- (2-butyn-acyl amino) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine (E-15) of preparation

Add HATU (32.3 mg, 0.085 mmol) to compound I-18 (25 mg, 0.065 mmol), diisopropylethylamine (40 μL, 0.197 mmol) and 2-butynoic acid ( 6.5 mg, 0.077 mmol (m) in dichloromethane (1 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC. Ilk parts containing the product were collected and then lyophilized to obtain 6.5 mg of 4 - {[6- (2-butyn-acyl amino) quinolin-4-yl] oxy} - N - (pyridin-2 Benzobenzamide ditrifluoroacetate (14% yield). Other salts or free bases of E-15 can be prepared by standard methods. LC-MS (Method A) Rt: 5.30 min; m / z 423.1 (M + H) +.

Example 32-4 - [(6 - {[ (2 E) -4- dimethylamine acyl-2-ene] amino} quinolin-4-yl] oxy} - N - (pyridin-2 -base) Preparation of benzamide (E-16)

Compound I-18 (20 mg, 0.056 mmol), 4-(dimethylamino)-2-butenoate (11.2 mg, 0.067 mmol) and EDCI (12.9 mg, 0.067 mmol) The suspension of tetrahydrofuran (1 ml) was stirred at 0&lt;0&gt;C, then pyridine (11 [mu]L, 0.135 <RTIgt; The reaction mixture was stirred at 0 ° C for 3 h and at rt overnight. The reaction mixture was diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The product was purified by using a vermiculite column chromatography with 10% methanol in dichloromethane as an eluent to give 16 mg of 4-[(6-{[( 2E )-4-dimethylamino) 2-en-acyl] amino} quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl-amine (61% yield) .LC-MS (method A) Rt: 4.06 min; m / z 468.2 (m + H) +; HPLC Rt:. 3.73 min ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm) = 2.19 (6H, S), 3.08 (2H, d, J = 6.0 Hz), 6.33 (1H, d, J = 15.4 Hz), 6.79 (1H, m), 7.18 (1H, m), 6.93 (1H, m), 7.37 (2H, d, J = 8.9 Hz), 7.86 (1H, m), 7.96 (1H, dd, J1 = 9.1 Hz, J2 = 2.3), 8.03 (1H, d, J = 9.5), 8.20 (3H, m), 8.40 (1H, m) , 8.66 (1H, d, J = 5.0), 8.79 (1H, d, J = 2.3 Hz), 10.50 (1H, s), 10.87 (1H, s).

Example 33-4-- [(6 - ((4-hydroxy-2-yn-acyl) amino) quinolin-4-yl) oxy] - N - (pyridin-2-yl) benzoyl amine ( Preparation of E-17)

Add triethylamine (77 μl, 0.55 mmol, 5 equivalents) to compound I-18 (40 mg, 0.11 mmol), T3P (50% ethyl acetate, 66 μL, 0.22 mmol) Ears, 2.0 equivalents) and 4-(tributyl-dimethyl-decyloxy)-but-2-ynoic acid (47 mg, 0.22 mmol, 2.0 equivalents) of tetrahydrofuran/NMP (4:1, In a solution of 3 ml), the dark brown solution was stirred at room temperature overnight. The reaction mixture was concentrated to a small amount, saturated aqueous ammonium chloride (aqueous) was added, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium s

The step of deprotecting the TBDMS: Concentrated hydrochloric acid (10 drops) was added to a solution of the brown oil in tetrahydrofuran (25 ml), and the suspension was stirred at room temperature for one hour. Saturated sodium hydrogencarbonate (aqueous) was added and the mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC using a LUNA (C18) 150 x 21.20 mm 5 micron column and a mobile phase 0 to 50% acetonitrile in water + trifluoroacetic acid to give a pale yellow solid 4-[(6- {[(2 E) -4- hydroxy - acyl-2-ynyl] amino} quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-ethyl) benzoyl-amine Ditrifluoroacetate (10.3 mg, 14%). Other salts or free bases of E-17 can be obtained by standard methods. LC-MS (Method A) Rt: 4.86 min; m/z 439.2 (M+H ⁺ , HPLC (method C) Rt: 5.22 points.

Preparation benzoyl amine (I-19) of (4-trifluoromethyl-pyridin-2-yl) - Example 34-4-- {[6- (methylamino) quinolin-4-yl] oxy} - N

4 - {[6- (nitro) quinolin-4-yl] oxy} - N - (4- trifluoromethyl-pyridin-2-yl) amine of the benzoyl. Suspension of compound I-9 (106 mg; 0.38 mmol), 4-chloro-6-nitroquinoline (75 mg; 0.36 mmol) and potassium carbonate (63 mg; 0.45) in acetonitrile (1 mL) The solution was stirred in a microwave oven at 150 ° C for 8 hours. The reaction mixture was diluted with ethyl acetate and then washed with water, saturated sodium hydrogen carbonate and brine. The organic layer was dried over sodium sulfate, filtered and evaporated The product was purified using silica gel chromatography (heptane / ethyl acetate = 2 / 3 v / v%) to give 71 mg of 4-{[6-(nitro)quinolin-4-yl]oxy} - N- (5-trifluoromethylpyridin-2-yl)benzamide (43%). LC-MS (Method A) Rt: 8.71 min; m / z 455.1 (M + H) +.

4 - {[6- (methylamino) quinolin-4-yl] oxy} - N - (4- trifluoromethyl-pyridin-2-yl) amine of the benzoyl. The Raney nickel was (suspension in ethanol, 50 mg) was added to 4 - {[6- (nitro) quinolin-4-yl] oxy} - N - (4- trifluoromethyl-pyridin-2-yl) A solution of benzamide (70 mg, 0.15 mmol) and ammonium formate (49 mg; 0.77 mmol) in ethyl acetate (4 mL) and ethanol (4 mL). The resulting mixture was stirred at 60 ° C for 6 hours. The reaction mixture was filtered over of dicalite, and the filtrate concentrated under reduced pressure, to obtain 80 mg of a brown solid form (quantitative) of 4 - {[6- (methylamino) quinolin-4-yl] oxy} - N -(4-Trifluoromethylpyridin-2-yl)benzamide. LC-MS (Method A) Rt: 5.85 min; m / z 425.1 (M + H) +.

Examples 35-4-- {[6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy} - N - (4- trifluoromethyl-pyridin-2-yl) benzoyl amine (E-18 Preparation

Acrylhydrazine chloride (4.7 μL, 0.058 mmol) was added to a solution of compound I-19 (20 mg, 0.052 mmol) in tetrahydrofurane (2 mL). The resulting mixture was stirred at -10 °C for 10 minutes. Diisopropylethylamine (11 μL, 0.065 mmol) was added to the resulting suspension. The resulting solution was stirred at -10 °C for 30 minutes and at room temperature for 3 hours. After evaporation, the residue was purified by preparative HPLC. Ilk parts containing the product were collected and then lyophilized to obtain 5.6 mg of 4 - {[6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy} - N - (4- trifluoromethyl-pyridin - 2-yl) benzamidine ditrifluoroacetate (15% yield). Other salts or free bases of E-18 can be prepared by standard methods. LC-MS (Method A) Rt: 6.45 min; m / z 479.2 (M + H) + 1 H NMR (400MHz, DMSO-D 6, 300K):. Δ (ppm) = 5.84 (1H, dd, J1 = 10.1Hz, J2=1.9Hz), 6.34 (1H, dd, J1=16.9Hz, J2=1.9Hz), 6.52 (1H, dd, J1=16.9Hz, J2=10.0Hz), 6.91(1H,d,J = 5.6 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.55 (1H, d, J = 5.1 Hz), 8.10 (2H, m), 8.26 (2H, d, J = 8.8 Hz), 8.58 ( 1H, s), 8.70 (1H, d, J = 5.1 Hz), 8.77 (1H, d, J = 5.7 Hz), 8.89 (1H, d, J = 1.9 Hz), 10.68 (1H, s), 11.40 ( 1H, s).

Examples 36-4-- {[6- (2-butyn-acyl amino) quinolin-4-yl] oxy} - N - (4- trifluoromethyl-pyridin-2-yl) benzoyl amine Preparation of (E-19)

Add HATU (23.7 mg, 0.062 mmol) to compound I-19 (20 mg, 0.047 mmol), diisopropylethylamine (30 μL, 0.165 mmol) and 2-butynoic acid ( 4.4 mg, 0.052 mmol) in dimethylformamide (1 ml). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered and evaporated The residue was purified by preparative HPLC. Ilk parts containing the product were collected and then lyophilized to obtain 1.5 mg of 4 - {[6- (2-butyn-acyl amino) quinolin-4-yl] oxy} - N - (4- trifluoromethyl Methylpyridin-2-yl)benzamide amine ditrifluoroacetate (4% yield). Other salts or free bases of E-19 can be prepared by standard methods. LC-MS (Method A) Rt: 6.63 min; m / z 491.1 (M + H) + 1 H NMR (400MHz, MeOD, 300K):. Δ (ppm) = 2.07 (3H, s), 6.94 (1H, d, J = 5.8 Hz), 7.44 (1H, m), 7.48 (2H, d, J = 8.8 Hz), 8.05 (2H, m), 8.21 (2H, d, J = 8.8 Hz), 8.61 (2H, m), 8.72 (2H, d, J = 5.8 Hz), 8.90 (1H, s).

Preparation benzoyl amine (I-20) of (4-ethyl-pyridin-2-yl) - Example 37-4-- {[6- (methylamino) quinolin-4-yl] oxy} - N

4 - {[6- (nitro) quinolin-4-yl] oxy} - N - (4- ethyl-pyridin-2-yl) amine of the benzoyl. Suspension of compound I-4 (115 mg; 0.46 mmol), 4-chloro-6-nitroquinoline (80 mg; 0.38 mmol) and potassium carbonate (95 mg; 0.69) in acetonitrile (1 mL) The solution was stirred in a microwave oven at 150 ° C for 8 hours. The reaction mixture was diluted with ethyl acetate and then washed with water, saturated sodium hydrogen carbonate and brine. The organic layer was dried over sodium sulfate, filtered and evaporated The product was purified using silica gel chromatography (heptane / ethyl acetate = 2 / 3 v / v%) to give &lt;RTI ID=0.0&gt; - N- (4-ethylpyridin-2-yl)benzamide (45%). LC-MS (Method A) Rt: 7.50 min; m / z 415.2 (M + H) +.

4 - {[6- (methylamino) quinolin-4-yl] oxy} - N - (4- ethyl-pyridin-2-yl) amine of the benzoyl. Palladium / carbon (10%, aqueous 50% humidity, catalytic amount) was added to 4 - {[6- (nitro) quinolin-4-yl] oxy} - N - (4- pyridin-2-ethyl A solution of benzamide (70 mg, 0.17 mmol) in ethyl acetate (4 mL) and ethanol (2 mL). The resulting mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered over of dicalite, and the filtrate concentrated under reduced pressure, to obtain 56 mg of a brown solid form 4 - {[6- (methylamino) quinolin-4-yl] oxy} - N - (4 -ethylpyridin-2-yl)benzamide (86%). This material was used directly in Example 38.

Examples 38-4-- {[6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-ethyl) benzoyl-amine (E-20) of the preparation

Acetylhydrazine chloride (4.7 μL, 0.058 mmol) was added to a solution of compound I-20 (19 mg, 0.049 mmol) in tetrahydrofurane (2 mL). The resulting mixture was stirred at -10 °C for 10 minutes. Diisopropylethylamine (4.5 microliters, 0.055 millimoles) was added to the resulting suspension. The resulting solution was stirred at -10 °C for 30 minutes and at room temperature for 3 hours. After evaporation, the residue was purified by preparative HPLC. Ilk parts containing the product were collected and then lyophilized to obtain 5.4 mg of 4 - {[6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy} - N - (4- pyridin-2-ethyl Benzobenzamide ditrifluoroacetate (16% yield). Other salts or free bases of E-20 can be prepared by standard methods. LC-MS (method A) Rt: 5.42 min; m/z 439.2 (M+H) +. ¹ H NMR (400 MHz, DMSO-D ₆ , 300K): δ (ppm) = 1, 23 (3H, t, J=7.6), 2.69 (2H, q, J=7.7), 5.85 (1H, dd, J1 = 10.2 Hz, J2 = 1.8 Hz), 6.33 (1H, dd, J1 = 17.1 Hz, J2 = 1.9 Hz), 6.51 (1H, dd, J1 = 17.0 Hz, J2 = 10.1 Hz), 6.93 (1H, d, J = 5.8 Hz), 7.10 (1H, d, J = 5.4 Hz), 7.48 (2H, d, J = 8.8) Hz), 8.09 (1H, s), 8.14 (1H, m), 8.26 (2H, d, J = 8.8), 8.30 (1H, d, J = 5.1 Hz), 8.82 (1H, d, J = 5.8 Hz) ), 8.93 (1H, s), 10.74 (1H, s), 10.92 (1H, s).

Examples 39-4-- {[6- (2-butyn-acyl amino) quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-ethyl) benzoyl-amine (E -21) Preparation

Add HATU (24.8 mg, 0.065 mmol) to compound I-20 (19 mg, 0.049 mmol), diisopropylethylamine (30 μL, 0.17 mmol) and 2-butynoic acid ( 4.6 mg, 0.054 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC. Ilk parts containing the product were collected and then lyophilized to obtain 6.8 mg of 4 - {[6- (2-butyn-acyl amino) quinolin-4-yl] oxy} - N - (4- ethyl Pyridin-2-yl)benzamide amine ditrifluoroacetate (22% yield). Other salts or free bases of E-21 can be prepared by standard methods. LC-MS (method A) Rt: 5.59 min; m/z 451.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-D6, 300K): δ (ppm) = 1, 23 (3H, t, J = 7.5), 2.09 (3H, s), 2.69 (2H, q, J = 7.5), 6.88 (1H, d, J = 5.7 Hz), 7.09 (1H, d, J = 5.2 Hz), 7.46 (2H, d, J = 8.7 Hz), 8.00 (1H, m), 8.10 (1H, m), 8.22 (2H, d, J = 8.9), 8.30 (1H, d, J = 5.4 Hz), 8.78 (1H, d , J = 5.5 Hz), 8.81 (1H, s), 10.90 (1H, s), 11.16 (1H, s).

Example 40-4 - [(6 - {[ (2 E) -4- dimethylamine acyl-2-ene] amino} quinolin-4-yl] oxy} - N - (4- B Preparation of pyridin-2-yl)benzamide (E-22)

Add chloroform (10 μL, 0.062 mmol) to 4-(dimethylamino)-2-butenoate (10.3 mg, 0.062 mmol) in acetonitrile (1 mL) and 1 Drop in N,N-dimethylformamide solution. The reaction mixture was stirred at 60 ° C for 30 minutes. A solution of Compound I-20 (20 mg, 0.052 mmol) in NMP (1 mL) was added dropwise to this solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with aq. sodium hydrogen sulfate. The organic layer was dried over sodium sulfate, filtered and evaporated. Water was added to the residue, centrifuged, and the supernatant was removed. This step is performed three times. Place the solid in two In the alkane, it was concentrated under reduced pressure. The residue was purified using preparative HPLC to give 2,5 mg of 4-[(6-{[( 2E )-4-dimethylaminobut-2-ylindolyl]amino}quinoline-4- yl] oxy} - N - (4- ethyl-pyridin-2-yl) benzoyl amine .LC-MS (method A) Rt: 4.43 min; m / z 496.2 (m + H) + 1 H NMR. (400MHz, MeOD, 300K): δ (ppm) = 1, 31 (3H, t, J = 7.5), 2.74 (2H, q, J = 7.7), 2.89 (6H, S) 3.95 (2H, d, J = 7.5 Hz), 6.60 (1H, d, J = 15.2 Hz), 6.74 (1H, m), 6.84 (1H, d, J = 5.2 Hz), 6.93 (1H, m), 7.07 (1H, d, J = 5.3 Hz), 7.40 (2H, d, J = 8.7), 7.97 (1H, d, J = 9.3), 8.04 (1H, d, J = 9.3), 8.12 (1H, s) 8.15 (2H, d, J = 8.9), 8.24 (1H, d, J = 5.3 Hz), 8.64 (1H, d, J = 5.3 Hz), 8.89 (1H, s).

Example 41-4 - [(6 - {[ (2 E) -4- N, N, N - trimethylammonium-2-en-acyl] amino} quinolin-4-yl] oxy} - Preparation of N- (5-ethylpyridin-2-yl)benzamide, iodide (E-23)

Methyl iodide (6 μL; 0.09 mmol) was added to a warm solution of compound E-22 (30 mg; 0.08 mmol) in tetrahydrofurane (2 mL). The mixture was stored in the refrigerator for three days. Almost all is converted to the desired product. The reaction mixture was concentrated under reduced pressure and ethyl acetate was added. The suspension was centrifuged and the supernatant was removed. The solid was suspended in ethyl acetate and centrifuged again. The supernatant was removed, and the solid was dried under reduced pressure to give 20 mg of 4-[(6-{[( 2E )-4- N,N,N -trimethylaminobutane-2 - ethenyl]amino}quinolin-4-yl]oxy}-N-(5-ethylpyridin-2-yl)benzamide, iodide. This ammonium iodide salt can be prepared using standard methods. Other suitable counter ions such as chloride and bromide exchange. LC-MS (method A) Rt: 4.71 min; m/z 511.2 (M+H) ⁺ ; HPLC (method C) Rt: 4.35 min; ¹ H NMR ( 400MHz, MeOD, 300K): δ (ppm) = 1, 31 (3H, t, J = 7.5), 2.74 (2H, q, J = 7.7), 2.89 (6H, S) 3.95 (2H, d, J = 7.5 Hz), 6.60 (1H, d, J = 15.2 Hz), 6.74 (1H, m), 6.84 (1H, d, J = 5.2 Hz), 6.93 (1H, m), 7.07 (1H, d, J = 5.3 Hz), 7.40 (2H, d, J = 8.7), 7.97 (1H, d, J = 9.3), 8.04 (1H, d, J = 9.3), 8.12 (1H, s) 8.15 (2H, d, J = 8.9), 8.24 (1H, d, J = 5.3 Hz), 8.64 (1H, d, J = 5.3 Hz), 8.89 (1H, s).

Example 42-4 - [(6 - {[ (2 E) -4- methoxy - acyl-2-ynyl] amino} quinolin-4-yl] oxy} - N - (4- B Preparation of pyridin-2-yl)benzamide (E-24)

Pyridine (21 μL, 0.26 mmol) was added to compound I-20 (50 mg, 0.13 mmol), 4-methoxy-2-butynoic acid (29.7 mg, 0.26 mmol) at room temperature. And EDCI (49.9 mg, 0.26 mmol) in tetrahydrofuran (2 mL) and NMP (1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was successively washed with an aqueous sodium hydrogencarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The product was purified using a vermiculite column chromatography using a gradient of 0-30% acetone in toluene as the eluent. Produce the product by two Lyophilized in an alkane to give 23 mg of 4-[(6-{[( 2E )-4-methoxy-but-2-ynindolyl]amino}quinolin-4-yl] oxy} - N - (4- ethyl-pyridin-2-yl) benzoyl amine .LC-MS (method A) Rt: 5.67 min; m / z 481.1 (m + H) +; HPLC ( method C) Rt: 6.74 minutes; ¹ H NMR (400 MHz, MeOD, 300K): δ (ppm) = 1, 31 (3H, t, J = 7.5), 2.74 (2H, q, J = 7.7), 2.89 (6H, S ) 3.95 (2H, d, J = 7.5 Hz), 6.60 (1H, d, J = 15.2 Hz), 6.74 (1H, m), 6.84 (1H, d, J = 5.2 Hz), 6.93 (1H, m) , 7.07 (1H, d, J = 5.3 Hz), 7.40 (2H, d, J = 8.7), 7.97 (1H, d, J = 9.3), 8.04 (1H, d, J = 9.3), 8.12 (1H, s) 8.15 (2H, d, J = 8.9), 8.24 (1H, d, J = 5.3 Hz), 8.64 (1H, d, J = 5.3 Hz), 8.89 (1H, s).

Preparation of (4-methyl-pyridin-2-yl) benzoyl amine (I-21) - A Example 43-4-- {[6- (methylamino) quinolin-4-yl] oxy} - N

4 - {[6- (nitro) quinolin-4-yl] oxy} - N - (4- methyl-pyridin-2-yl) amine of the benzoyl. Compound I-3 (229 mg; 1.00 mmol), 4-chloro-6-nitroquinoline (200 mg; 0.96 mmol) and N,N-dimethyl carbonate (394 mg; 1.21) A suspension of carbamide (2 ml) was stirred at 50 ° C overnight. The reaction mixture was poured into 20 ml of water and stirred for additional 1 hour. The solid was filtered off and dried under reduced pressure overnight to yield 340 mg of 4-{[6-(nitro)quinolin-4-yl]oxy}-N-(4-methylpyridine-2 -yl)benzamide (89%). LC-MS (Method A) Rt: 6.90 min; m / z 401.2 (M + H) +.

4 - {[6- (methylamino) quinolin-4-yl] oxy} - N - (4- methyl-pyridin-2-yl) amine of the benzoyl. Iron (664 mg; 11.89 mmol) was added to 4 - {[6- (nitro) quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-methyl) benzoyl A solution of the amine (340 mg, 0.85 mmol) in tetrahydrofuran (20 mL) and acetic acid (49 [mu]L; 0.85 mmol). The resulting mixture was stirred at reflux for 4 h, then additional acetic acid (486 [mu]L; 8.49 m. The reaction mixture was stirred at reflux overnight. The reaction mixture was poured into a 10% ammonia solution and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate The product was purified using silica gel chromatography (dichloromethane/methanol = 95/5 v/v%) to give &lt;RTI ID=0.0&gt; oxy} - N - (4- pyridin-2-yl-methyl) benzoyl amine. LC-MS (Method A) Rt: 4.45 min; m / z 371.2 (M + H) +.

Examples 44-4-- {[6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-methyl) benzoyl-amine (E-25) of preparation

Suspension of compound I-21 (20 mg, 0.054 mmol), acrylic acid (7.4 μL, 0.081 mmol) and EDCI (15.5 mg, 0.081 mmol) in tetrahydrofuran (1 mL) and NMP (1 mL) The solution was stirred at room temperature then pyridine (13 [mu]L, 0.162 <RTIgt; The reaction mixture was stirred at room temperature overnight. Additional EDCI (0.5 eq.) and acrylic acid (0.5 eq.) were added and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate and washed with water, saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The product was purified by chromatography on a gradient of 0-5% methanol in dichloromethane. Parts of the pure fractions concentrated under reduced pressure, and then from acetonitrile and water and lyophilized to obtain 10 mg of 4 - {[6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy} - N - ( 4-methylpyridin-2-yl)benzamide (44%). LC-MS (method A) Rt: 4.98 min; m/z 425.2 (M+H) ⁺ ; ESI (ESI C) Rt: 5.49 min, ¹ H NMR (400 MHz, DMSO-D6, 300K): δ (ppm) =1, 23 (3H, t, J = 7.6), 2.69 (2H, q, J = 7.7), 5.85 (1H, dd, J1 = 10.2 Hz, J2 = 1.8 Hz), 6.33 (1H, dd, J1 = 17.1 Hz, J2 = 1.9 Hz), 6.51 (1H, dd, J1 = 17.0 Hz, J2 = 10.1 Hz), 6.93 (1H, d, J = 5.8 Hz), 7.10 (1H, d, J = 5.4 Hz), 7.48 (2H, d, J = 8.8 Hz), 8.09 (1H, s), 8.14 (1H, m), 8.26 (2H, d, J = 8.8), 8.30 (1H, d, J = 5.1 Hz), 8.82 (1H, d, J = 5.8 Hz), 8.93 (1H, s), 10.74 (1H, s), 10.92 (1H, s).

Examples 45-4-- {[6- (2-butyn-acyl amino) quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-methyl) benzoyl-amine (E -26) Preparation

This compound was obtained from the compound I-21 and butynoic acid to give the title compound (1.7 mg, 7%). LC-MS (method A) Rt: 5.15 min; m/z 437.2 (M+H) ^+. HPLC (Method C) Rt: 5.90.

Example 46-4 - [(6 - {[ (2 E) -4- dimethylamine acyl-2-ene] amino} quinolin-4-yl] oxy} - N - (4- methyl Preparation of pyridin-2-yl)benzamide (E-27)

This compound was prepared from the compound I-21 and 4-(dimethylamino)-2-butenoic acid salt to give the title compound (2.8 mg, 11). %). LC-MS (Method A) Rt: 4.05 min; m / z 482.2 (M + H) + .HPLC ( Method C) Rt: 3.96 min.

Example 47-4-[(6-{[( E/Z )-4- Preparation benzoyl amine (E-28) of (pyridin-2-yl) - but-2-en-morpholino acyl] amino} quinolin-4-yl) oxy] - N

4 - [(6 - {[ (E / Z) -4- bromo-but-2-en-acyl] amino} -4-quinolinyl) oxy] - N - (2- pyridyl) benzoyl Preparation of amines. Add chloroform (285 μl, 3.40 mmol) and a few drops of N,N-dimethylformamide to 4-bromocrotonic acid (500 mg, 3.03 mmol) in dichloromethane (5 mL) ) in solution. The reaction was stirred at room temperature for 1.5 hours. The solvent and excess reagent were removed under reduced pressure. The residue was dissolved in EtOAc (1 mL) (EtOAc) The reaction was stirred at 0 ° C for 3 hours. Water was added to the reaction mixture and the product was extracted into dichloromethane. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was suspended in ethanol and ethyl acetate. The solid was filtered off to give 117 mg of 15% yield of desired mixture of chloride and bromide. The filtrate was concentrated under reduced pressure, then the crude material on silica 0-10% methanol / dichloromethane elution chromatography, to yield 4 - [(6 - {[ (E / Z) -4- bromo- acyl-2-enyl] amino} -4-quinolinyl) oxy] - N - (2- pyridyl) benzoyl-amine (314 mg, 40%; purity = 83%.

4-[(6-{[( E/Z )-4- Morpholino-2-en acyl] amino} quinolin-4-yl) oxy] - N - (pyridin-2-yl) amine of the benzoyl. At 0 ° C will Phenogen (20 mg, 0.23 mmol) is added to 4-[(6-{[( E/Z )-4-bromobut-2-enyl]amino}-4-quinolinyl)oxy] - N - (2- pyridyl) benzoyl-amine (58 mg, 0.12 mmol) and triethylamine (0.048 ml, 0.35 mmol) of 1 ml N, N- dimethylformamide solution . The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC eluting with EtOAc EtOAc. The pure fraction was poured onto the SCX2 column and washed with 10% DIPEA in methanol. The compound was lyophilized from water to give 9.8 mg (17%) of a pale yellow solid 4-[(6-{[( E/Z )-4- Morpholino-2-en acyl] amino} quinolin-4-yl) oxy] - N - (pyridin-2-yl) benzoyl amine. LC-MS (method A) Rt: 3.00 min; m/z 510.1 (M+H) ⁺ ; HPLC (Method C) Rt: 4.12.

Preparation of Example 48-( E )-4-[2-Methoxyethyl(methyl)amino]but-2-enoic Acid (I-22)

Preparation of (E)-4-[2-methoxyethyl(methyl)amino]but-2-enoate methyl ester. Add 4-trans-bromomethyl crotonate (1 g; 5.6 mmol) to a solution of N-(2-methoxyethyl)methylamine (1.1 g; 12.3 mmol) in 25 mL of tetrahydrofuran The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (25 mL). It was then washed six times with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give ( E )-4-[2-methoxyethyl(methyl)amino]butyl-2 Methyl enoate (895 mg, 86%).

Preparation of ( E )-4-[2-methoxyethyl(methyl)amino]but-2-enoic acid. Add lithium hydroxide monohydrate (LiOH.H ₂ O, 420 mg, 10 mmol) to ( E )-4-[2-methoxyethyl(methyl)amino]but-2-ene acid methyl ester (895 mg, 4.8 mmol) of tetrahydrofuran / H ₂ O (20mL / 20 mL) and the mixture stirred for 12 hours at 25 deg.] C. The pH of the mixture was then adjusted to about 7. The solvent was removed under reduced pressure to give the crude product ( E )-4-[2-methoxyethyl(methyl)amino]but-2-enoic acid (1.8 g). The product was placed in toluene and the salt was filtered off. The filtrate was concentrated under reduced pressure. The residue was taken up in 10 ml of isopropanol, and then 10 ml of diethyl ether was slowly added. The solid was filtered off and washed with diethyl ether to give ( E )-4-[2-methoxyethyl(methyl)amino]but-2-enoic acid as a white hygroscopic solid. Mg; 49%). The filtrate was concentrated under reduced pressure. The residue was taken up in 5 ml of isopropanol and then 15 ml of diethyl ether was slowly added. The supernatant liquid was removed, and the solid was dried under reduced pressure to obtain ( E )-4-[2-methoxyethyl(methyl)amino]butyl-2 as a white hygroscopic solid. -enoic acid (466 mg, 56%) (56%). LC-MS (Method A) Rt: 0.70 min; m / z 174.1 (M + H) +.

Example 49-4-{[6-{[( E )-4-[2-methoxyethyl(methyl)amino]but-2-enyl]amino}quinolin-4-yl] (E-29) preparation of (4-ethyl-pyridin-2-yl) benzoyl amine - oxy} - N

Pyridine (21 μL; 0.26 mmol) was added to compound I-20 (50 mg; 0.13 mmol), compound I-22 (45 mg; 0.26 mmol) and EDCI (50 mg; 0.26 mmol) In a solution of tetrahydrofuran (2 ml). The reaction mixture was stirred at room temperature for 1 hour. 1 ml of N,N-dimethylformamide was added, followed by I-22 (45 mg; 0.26 mmol), EDCI (50 mg; 0.26 mmol) and pyridine (21 μL; 0.26 mmol) The ear was added and the reaction mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC eluting with a gradient of 0-100% acetonitrile (trifluoroacetic acid). The pure fractions were washed with tetrahydrofuran and an aqueous sodium bicarbonate solution saturated with sodium chloride. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was placed in water and lyophilized to give 21 mg of brown solid 4-{[6-{[( E )-4-[2-methoxyethyl(methyl)amino]butyl-2 - alkenyl acyl] amino} quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-ethyl) benzoyl-amine (30%). LC-MS (method A) Rt: 3.50 min; m/z 540.2 (M+H) ⁺ ; HPLC (Method C) Rt: 5.00.

Example Preparation of 50-4-methylbenzenesulfonic acid [(3 S )-tetrahydrofuran-3-yl]ester (I-23)

At 0 ℃ benzene sulfonic acyl chloride (601 mg, 3.4 mmol) was added to (3 S) - tetrahydrofuran-3-ol (193 [mu] L, 2.8 mmol) of pyridine (5 mL). The reaction mixture was stirred at 0 ° C for 1 hour and at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by EtOAc EtOAc EtOAc. Pure fractions were collected, to obtain 275 mg of a colorless oil of 4-methylbenzenesulfonic acid [(3 S) - tetrahydrofuran-3-yl] ester (40%). This material was used directly in the next step.

Examples 51-4-- {[6-amino -7 - {[(3 R) - tetrahydrofuran-3-yl] oxy} quinolin-4-yl] oxy} - N - (pyridin-2-yl) Preparation of benzamide (I-24)

4 - {[6-nitro -7 - {[(3 R) - tetrahydrofuran-3-yl] oxy} quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl Preparation of amines. N,N-dimethylformamidine of compound I-15 (100 mg, 0.25 mmol), potassium carbonate (86 mg, 0.62 mmol) and compound I-23 (66 mg, 0.27 mmol) The amine (1 ml) suspension was stirred at 50 °C overnight. Approximately 70% conversion to the desired product was observed. The reaction mixture was stirred at 60 ° C for 8 hours and stored in a freezer over the weekend. The reaction mixture was stirred at 60 ° C for 4 hours. The reaction mixture was diluted with ethyl acetate and brine and brine brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography eluting with 0-5% methanol in dichloromethane to yield 66 mg 4-{[6 - nitro -7 - {[(3R) - tetrahydrofuran-3-yl] oxy} quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl-amine (56%). LC-MS (Method A) Rt: 5.31 min; m / z 473.1 (M + H) +.

4 - {- [6- amino -7 - {[(3 R) - tetrahydrofuran-3-yl] oxy} quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl Preparation of amines. Palladium / carbon (25 mg) was added to 4 - {[6-nitro -7 - {[(3 R) - tetrahydrofuran-3-yl] oxy} quinolin-4-yl] oxy} - N - A solution of (pyridin-2-yl)benzamide (66 mg, 0.14 mmol) in ethanol (5 ml) and THF (5 ml), and the mixture was stirred at 60 ° C for 4 hours under hydrogen atmosphere. . The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. The residue was purified by rubble column chromatography eluting with a gradient of 0 to 5% methanol in dichloromethane to give 4-{[6-amino-7-{[(3 R )-tetrahydrofuran-3-yl]oxy}quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide (40 mg, 0.0841 mmol, 60.2% yield). LC-MS (Method A) Rt: 3.77 min; m / z 443.1 (M + H) +.

Example 52-4-{[6-(but-2-ynindolyl)-7-{[(3 R )-tetrahydrofuran-3-yl]oxy}quinolin-4-yl]oxy}- Preparation of N- (pyridin-2-yl)benzamide (E-30)

This was obtained from the title compound (21 mg, 52%) LC-MS (method A) Rt: 4.33 min; m/z 509.1 (M+H) ⁺ , HPLC (method C) Rt: 6.43.

Example 53-4-- [(6- (4-methoxy-2-yn-acyl) (methyl) amino quinolin-4-yl) oxy] - N - (4- methyl-2 -base) Preparation of benzamide (E-31)

Preparation of 4-[(6-(methyl)aminoquinolin-4-yl)oxy]-N-(4-methylpyridin-2-yl)benzamide. A suspension of compound I-21 (85 mg; 0.23 mmol) and polyformaldehyde (21 mg; 0.69 mmol) in methanol (2 mL) was warmed to 70 ° C for 2 hr. The reaction mixture was cooled to room temperature and then filtered to remove excess polyoxymethylene. Sodium cyanoborohydride (14 mg; 0.23 mmol) was added and the mixture was stirred at room temperature for 17 h. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was concentrated in vacuo. The crude product was purified by preparative HPLC. The product-containing fraction was concentrated to give 20 mg of 4-[(6-(methyl)aminoquinolin-4-yl)oxy]-N-(4-methylpyridin-2-yl)benzene. Indoleamine (23% yield).

4-[(6-(4-Methoxybut-2-ynindolyl)(methyl)aminoquinolin-4-yl)oxy]-N-(4-methylpyridin-2-yl) Preparation of benzamide ditrifluoroacetate. 4-methoxybut-2-ynoic acid (12 mg; 0.104 mmol), pyridine (8.4 μL; 0.104 mmol) and EDCI (20 mg; 0.104 mmol) were added to 4-[( 6- (methyl) amino quinolin-4-yl) oxy] - N - (4- pyridin-2-yl-methyl) benzoyl-amine (20 mg; 0.052 mmol) of tetrahydrofuran (2 ml ) in solution. The mixture was stirred at room temperature for 3 hours. 4-methoxybut-2-ynoic acid (12 mg; 0.104 mmol), pyridine (8.4 μl; 0.104 mmol) and EDCI (20 mg; 0.104 mmol) together with 400 μl of NMP Join. Stirring was continued for 17 hours. Add 500 microliters of water. The tetrahydrofuran was removed in vacuo and the residue was purified by preparative HPLC. The product-containing fraction was concentrated and lyophilized to give 4.9 mg of 4-[(6-(4-methoxybut-2-ynindolyl)(methyl)aminoquinolin-4-yl)oxy yl] - N - (4- pyridin-2-yl-methyl) benzoyl-amine trifluoroacetate 1: 2 (20% yield). Other salts or free bases of E-31 can be prepared by standard methods. LC-MS (method A) Rt: 5.58 min; m/z 481.1 (M+H) ^+. HPLC (Method C) Rt 6.56.

Example 54-4- Preparation of porphyrin-2-ynoic acid (I-25)

4-(1-methylprop-2-ynyl) Preparation of porphyrins. 3-Bromobut-1-yne (1 g, 7,52 mmol), potassium carbonate (0.57 g; 4.14 mmol) and The porphyrin (0.65 mL; 7.52 mmol) was taken in MeOH (10 mL) and then evaporated. 3-Bromobut-1-yne (1 g; 7.52 mmol) was added dropwise with stirring. After 30 minutes, the ice bath was removed and stirred at room temperature overnight to give an off-white suspension. The precipitated salt was removed by filtration. The filtrate was evaporated to dryness then treated with dichloromethane to give another suspension. The precipitate was removed by filtration and the filtrate was evaporated again to dryness then ethyl ether. This has another precipitate. After the final filtration/evaporation step, the product was obtained as a yellow oil (320 mg; 30% yield).

4- Preparation of morphopent-2-ynoic acid. 4-(1-methylprop-2-ynyl) under nitrogen The porphyrin (320 mg; 2.3 mmol) was dissolved in tetrahydrofuran (10 mL) and then cooled to -78. A solution of n-butyllithium in hexane (1.44 mL; 2.3 mmol) was added dropwise with stirring. After 1 hour, the crushed carbon dioxide (2023 mg; 45.98 mmol) was added in one portion, after which the mixture was allowed to come to room temperature. Water and ethyl acetate were added to the mixture and the layers were separated. The aqueous layer was then evaporated to dryness. The crude product was dissolved in methanol. The insoluble salt is separated by filtration, and then the solution is evaporated to dryness to obtain a yellow solid. Oletopent-2-ynoic acid (405 mg; 2.21 mmol; 96% yield).

Example 55-4-- [(6-amino-quinazolin-4-yl) oxy] - N - [4- (ethyl) pyridin-2-yl] benzoyl-amine (I-26) Preparation of

4 - [(6-nitro quinazolin-4-yl) oxy] - N - [4- (ethyl) pyridin-2-yl] benzoyl preparation of amines. Compound I-4 (450 mg; 1.90 mmol), 4-chloro-6-nitroquinoline (410 mg; 2.00 mmol) and potassium carbonate (260 mg; 2.00 mmol) of acetonitrile (5) The solution was stirred in a microwave oven at 135 ° C for 45 minutes and then at 150 ° C for 1 hour. The reaction was filtered, washed with water and then with acetonitrile, taken up in toluene, and then co-evaporated twice, to obtain 88 mg of 4 - [(6-nitro quinazolin-4-yl) oxy] - N - [4 -(Ethyl)pyridin-2-yl]benzamide (11%).

4 - [(6-amino-quinazolin-4-yl) oxy] - N - [4- (ethyl) pyridin-2-yl] benzoyl amine. Adding a Rex nickel suspension (80 mg) to 4-[(6-nitroquinazolin-4-yl)oxy]-N-[4-(ethyl)pyridin-2-yl]benzamide Amine (88 mg; 0.21 mmol) and ammonium formate (80 mg; 1.27 mmol) in ethyl acetate and ethanol. The reaction mixture was stirred at 60 ° C for 1 hour. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. The residue was purified by preparative HPLC eluting with a gradient of 0-100% acetonitrile (trifluoroacetic acid). Pure fractions were collected, to yield 3.6 mg of 4 - [(6-amino-quinazolin-4-yl) oxy] - N - [4- (trifluoromethyl) pyridin-2-yl] benzoyl amine (4%).

Examples 56-4-- {[6- (Bingxi Xi-ylamino) quinazolin-4-yl] oxy} - N - [4- (ethyl) pyridin-2-yl] benzoyl amine (E- 32) Preparation

This compound was prepared from the compound I-26 and EtOAc (m.p. Other salts or free bases of E-32 can be prepared by standard methods. LC-MS (method A) Rt: 6.26 min; m/z 440.5 (M+H) ⁺ HPLC (Method C) Rt 7.14.

Example 57 Preparation of 4-[(6-Nitroquinolin-4-yl)amino]benzoic acid (I-27)

4-Chloro-6-nitroquinoline (2.876 mmol, 600 mg) and 4-aminobenzoic acid (3.020 mmol, 414 mg) were suspended in ethanol (15 mL). After about 25 drops of concentrated hydrochloric acid (37%, catalytic amount) were added, the reaction was stirred at reflux for 3 hours. The reaction mixture was cooled to room temperature and the solid was filtered. The solid was washed with ethanol and dried in vacuo to give EtOAc (EtOAc) LC-MS (Method A) Rt: 4.398 min; m / z 310.1 (M + H) +.

Preparation benzoyl amine (I-28) of (pyridin-2-yl) - Example 58-4- [6-amino-quinolin-4-yl) amino] - N

4- [6-nitro-quinolin-4-yl) amino] - N - (pyridin-2-yl) amine of the benzoyl. Compound I-27 (0.266 mmol, 82 mg), 2-aminopyridine (0.292 mmol, 28 mg), EDCI (0.399 mmol, 76 mg) and DMAP (0.032 mmol, 4 mg) The mixture was combined in a flask and redissolved in a mixture of dichloromethane and NMP (2/1 v/v%) (2 ml). The reaction mixture was concentrated, water was added, and the mixture was centrifuged. Remove the supernatant, then rinse the solid with water and place it in two In the alkane, concentrate in vacuo. The residue was purified by chromatography on silicon dioxide (0-8% of methanol in dichloromethane) to be purified, to obtain 55 mg of 4- [6-nitro-quinolin-4-yl) amino] - N - ( Pyridin-2-yl)benzamide (54%). LC-MS (Method A) Rt: 4.731 min; m / z 386.1 (M + H) +.

Preparation of 4-[6-aminoquinolin-4-yl)amino]-N-(pyridin-2-yl)benzamide. 4-[6-Nitroquinolin-4-yl)amino]-N-(pyridin-2-yl)benzamide (55 mg, 0.143 mmol) dissolved in ethyl acetate and ethanol Liquid (2/1 v/v%) (6 ml). The solution was purged with nitrogen, after which a catalytic amount of palladium on carbon (10%, wet) was added. The reaction mixture was again purged with nitrogen, then stirred at room temperature under a hydrogen atmosphere overnight. The reaction mixture was filtered on EtOAc (EtOAc m.). Formamide (100%). LC-MS (Method A) Rt: 4.425 min; m / z 356.2 (M + H) +.

Examples 59-4-- {[6- (2-ynyl acyl group) quinolin-4-yl] amino} - N - (pyridin-2-yl) benzoyl amine (E-33) of preparation

Compound I-28 (0.071 mmol, 25 mg), HATU (0.094 mmol, 36 mg) and 2-butenoic acid (0.079 mmol, 7 mg) were suspended in 1.5 mL dichloromethane. DIPEA (0.250 millimolar, 41 microliters) was added. The reaction mixture was stirred at room temperature overnight. After concentrating the mixture in vacuo, the residue was eluted with a mixture of methanol/water (1/1 v/v%) by Strong Cation Exchange (SCX2), and then rinsed with 10 v/v% DIPEA in methanol. It was purified to give a crude product. The crude product was purified using semi-preparative HPLC. The product containing ilk parts concentrated in vacuo, to obtain 9 mg of 4 - {[6- (2-ynyl acyl group) quinolin-4-yl] amino} - N - (pyridin-2 Benzobenzamide (20%) trifluoroacetate. Other salts or free bases of E-33 can be prepared by standard methods. LC-MS (Method A) Rt: 4.978 min; m / z 211.7 ((M + H) / 2) +.

Preparation benzoyl amine (E-34) of (pyridin-2-yl) - Example 60-4-- {[6- (Bingxi Xi-ylamino) quinolin-4-yl] amino} - N

Compound I-28 (0.026 mmol, 9 mg), EDCI (0.052 mmol, 10 mg) and acrylic acid (0.052 mmol, 3,5 μL) were suspended in a mixture of tetrahydrofuran and NMP (1/ 1 v/v%). Pyridine (0.104 mmol, 8 μl) was added. The reaction mixture was stirred at room temperature overnight. After concentration, the reaction of the mixture was quenched with a small amount of water and diluted with methanol. The solution was subjected to a Strong Cation Exchange (SCX2) using a methanol/water mixture (1/1 v/v%) as an eluent, followed by rinsing with 10 v/v% DIPEA in methanol to give a crude product. The crude product was purified using semi-preparative HPLC. The product-containing fraction was concentrated in vacuo to give 3 mg of 4-{[6-(propenylamino)quinolin-4-yl]amino}-N-(pyridin-2-yl)benzene. Indoleamine (25%). LC-MS (Method A) Rt: 4.445; m/z: 410.2 (M+H) ⁺ , HPLC (A) Rt: 4.531.

Preparation benzoyl amine (I-29) of (4-methyl-pyridin-2-yl) - Example 61-4-- [(6-amino-quinolin-4-yl) amino] - N

The title compound was prepared using the method of the compound-28 I synthesis, i.e. quantitative yield to give 52 mg of 4 - [(6-amino-quinolin-4-yl) amino] - N - (4- methyl Pyridin-2-yl)benzamide. LC-MS (Method A) Rt: 4.367 min; m / z 370.2 (M + H) +.

Examples 62-4-- {[6- (2-ynyl acyl group) quinolin-4-yl] amino} - N - (4- pyridin-2-yl-methyl) benzoyl-amine (E -35) Preparation

Compound I-29 (0.052 mmol, 19 mg), HATU (0.069 mmol, 26 mg) and 2-butenoic acid (0.057 mmol, 5 mg) were suspended in 1.5 mL dichloromethane. DIPEA (0.183 millimolar, 30 microliters) was added. The reaction mixture was stirred at room temperature overnight. After concentrating the mixture in vacuo, the residue was eluted with a mixture of methanol/water (1/1 v/v%) by Strong Cation Exchange (SCX2), and then rinsed with 10 v/v% DIPEA in methanol. It was purified to give a crude product. The crude product was purified using semi-preparative HPLC. The product containing ilk parts concentrated in vacuo, to yield 7 mg of 4 - {[6- (2-ynyl acyl group) quinolin-4-yl] amino} - N - (4- methyl Pyridin-2-yl)benzimidamide ditrifluoroacetate (19%). Other salts or free bases of E-35 can be prepared by standard methods. LC-MS (method A) Rt: 4.843, m/z: 436.2 (M+H) ⁺ , HPLC (Method C) Rt: 4.655.

Examples 63-4-- {[6- (Bingxi Xi-ylamino) quinolin-4-yl] amino} - N - (4- pyridin-2-yl-methyl) benzoyl-amine (E-36) of preparation

Compound I-29 (0.048 mmol, 18 mg) was dissolved in 1 mL dichloromethane. DIPEA was added and the mixture was cooled to 0 °C. Acrylhydrazine chloride was added, and the reaction mixture was stirred at 0 ° C for 4 hours. After concentrating the mixture in vacuo, the residue was eluted with a mixture of methanol/water (1/1 v/v%) by Strong Cation Exchange (SCX2), and then rinsed with 10 v/v% DIPEA in methanol. It was purified to give a crude product. The crude product was purified using semi-preparative HPLC. The product containing ilk parts concentrated in vacuo, to obtain 9 mg of 4 - {[6- (Bingxi Xi-ylamino) quinolin-4-yl] amino} - N - (4- methyl-2- Benzobenzamide ditrifluoroacetate (27%). Other salts or free bases of E-36 can be prepared by standard methods. LC-MS (method A) Rt: 4.735 min; m/z 424.2 (M+H) ⁺ , HPLC (Method C) Rt: 4.396.

Preparation benzoyl amine (I-30) of (4-ethyl-pyridin-2-yl) - Example 64-4-- [(6-amino-quinolin-4-yl) amino] - N

The title compound using the method of preparation of compound I-29, i.e., to obtain 69 mg of 4 - [(6-amino-quinolin-4-yl) amino] - N - (4- pyridin-2-yl-ethyl Benzoguanamine (86%). LC-MS (Method A) Rt: 5.029 min; m / z 192.6 ((M + H) / 2) +.

Examples 65-4-- {[6- (Bingxi Xi-ylamino) quinolin-4-yl] amino} - N - (4- pyridin-2-yl-ethyl) benzoyl-amine (E-37) of preparation

The title compound using the method of preparation of compound E-34, to obtain 4 mg of 4 - {[6- (Bingxi Xi-ylamino) quinolin-4-yl] amino} - N - (4- ethyl Pyridin-2-yl)benzamide (15%). LC-MS (Method A) Rt: 5.263; m/z 438.2 (M+H) ⁺ , HPLC (Method C) Rt:5.215.

Examples 66-4-- {[6 - ((4-methoxy-2-yn-acyl) amino) quinolin-4-yl] amino} - N - (4- pyridin-2-yl-ethyl Preparation of benzoguanamine (E-38)

The title compound was synthesized by the method described for the preparation of compound E-34 to give 3 mg of 4-{[6-((4-methoxybut-2-ynindolyl)amino)quinolin-4-yl] amino} - N - (4- pyridin-2-yl-ethyl) benzoyl-amine (7%). LC-MS (method A) Rt: 5.977 min; m/z 240.7 ((M+H)/2)+, HPLC (Method C) Rt: 5.579.

Example 67 Preparation of 4-chloro-7-methoxy-6-nitroquinoline (I-31)

5-{( E )-[(3-methoxy-4-nitrophenyl)imino]methyl}-2,2-dimethyl-1,3-di Preparation of alkane-4,6-dione. 3-methoxy-4-nitroaniline (3,75 g, 18,7 mmol) and 5-(ethoxymethylene)-2,2-dimethyl-1,3-di The alkane-4,6-dione (3,15 g, 18,7 mmol) was suspended in ethanol (100 mL) and stirred at 85 ° C for 1 hour. The reaction mixture was cooled to room temperature. The solid was filtered off, washed with EtOAc (EtOAc)EtOAc. This material was used directly in the next step.

Preparation of 7-methoxy-6-nitroquinolin-4-ol. 5-{( E )-[(3-methoxy-4-nitrophenyl)imino]methyl}-2,2-dimethyl-1,3-di Alkane-4,6-dione (5.82 g, 18,1 mmol) was suspended in diphenyl ether (50 mL). The reaction mixture was stirred at 220 ° C for 1 hour. The mixture was cooled to room temperature and filtered. The residual solid was washed with dichloromethane and tetrahydrofuran. The product was then washed from the filter using a gradient of 20-50% methanol in dichloromethane. The obtained product was concentrated to give the title compound (68%). ¹ H NMR (400 MHz, DMSO-d ₆ , 300K): δ=3.99 (3H, s), 6.06 (1H, d, J = 7.6 Hz), 7.19 (1H, s), 7.95 (1H, d, J = 7.6 Hz), 8.53 (1H, s), 11.90 (1H, br s)

Preparation of 4-chloro-7-methoxy-6-nitroquinoline. 7-Methoxy-6-nitroquinolin-4-ol (2.7 g, 12.3 mmol) was suspended in sulfoxide (50 mL). A small amount of N,N-dimethylformamide (0.5 ml) was added and the mixture was stirred at reflux for 4 hr. The reaction mixture was concentrated in vacuo and then evaporated twice with toluene to afford a brown solid which was dried on oil. The crude product was triturated with diethyl ether and the solid obtained was dried in vacuo to give a yellow/light brown solid. LC-MS (method B) Rt: 7.449; m/z 239.1 (M+H)+.

Preparation benzoyl amine (I-33) of (pyridin-2-yl) - Example 68-4-- [(6-amino-7-methoxy-quinolin-4-yl) oxy] - N

4 - [(6-nitro-7-methoxy-quinolin-4-yl) oxy] - N - (pyridin --2- yl) benzoyl amine of preparation. Compound I-32 (4.19 mmol, 1.00 g), compound I-1 (4.61 mmol, 0.99 g) and potassium tributylbutoxide (7.12 mmol, 0.80 g) of NMP (4 mL) A suspension of tetrahydrofuran (16 ml) was stirred in a microwave oven at 150 ° C for 2 hours. The reaction mixture was diluted with EtOAc EtOAc EtOAc. The crude product was purified by silica gel chromatography using a gradient of 0-40% acetone in toluene. The pure fractions were combined and evaporated to dryness afforded EtOAc EtOAc EtOAc LC-MS (Method B) Rt: 7.040 min; m / z 417.1 (M + H) +.

4 - [(6-amino-7-methoxy-quinolin-4-yl) oxy] - N - (pyridin-2-yl) amine of the benzoyl. 4 - [(6-nitro-7-methoxy-quinolin-4-yl) oxy] - N - (pyridin-2-yl) benzoyl-amine (2.09 mmol, 870 mg) in tetrahydrofuran of The /ethanol (75 ml, 2/1 v/v%) solution was flushed with nitrogen. Palladium on carbon (10%, wet, excess) was added and the mixture was again purged with nitrogen. The mixture was stirred at room temperature overnight while blowing a stream of hydrogen into the mixture. The palladium/carbon was removed by filtration on Dicalite and the filtrate was concentrated in vacuo. The crude product was purified by chromatography eluting with a gradient of 0-10% methanol in dichloromethane. The fractions were combined and concentrated in vacuo to give titled </ LC-MS (Method B) Rt: 4.961 min; m / z 387.1 (M + H) +.

Examples 69-4-- {[6- (acyl-2-ynyl) -7-methoxy-quinolin-4-yl] amino} - N - (pyridin-2-yl) benzoyl amine Preparation of (E-39)

A solution of compound I-33 (0.194 mmol, 75 mg) and 2-butynoic acid (0.388 mmol, 32 mg) in pyridine (1.5 mL) was taken in EDCI (0.776 m. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness to give a red brown oil. The crude product was purified by preparative HPLC (Luna C-18) eluting with gradient 0-50% EtOAc in EtOAc EtOAc. The fractions containing the product were saturated with sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give a pale-white solid solid, which was re-processed to a fine powder by sonication in diethyl ether, followed by filtration to obtain 38 mg (43%) of off-white. The title compound of the solid form. LC-MS (method A) Rt: 3.828 min; m/z 453.2 (M+H)+, HPLC (method C) Rt: 5.908, ¹ H NMR (400 MHz, DMSO-d6, 300K): δ (ppm) =2.05(3H,s),4.03(3H,s),6.66(1H,d,J=5.1Hz), 7.17(1H,t,J=4.8Hz),7.36(2H,d,J=8.8Hz) , 7.51 (1H, s), 7.85 (1H, t, J = 8 Hz), 8.18 (3H, m), 8.40 (1H, m), 8.63 (1H, d, J = 5.1 Hz), 8.74 (1H, s ), 9.85 (1H, s), 10.8 (1H, s).

Examples 70-4-- {[6 - ((4-methoxy-2-yn-acyl) amino) -7-methoxy-quinolin-4-yl] amino} - N - (4- B Preparation of pyridin-2-yl)benzamide (E-40)

1-Propanephosphonic acid cyclic anhydride (50% by weight of ethyl acetate) (0.137 mmol, 41 μL) was added to compound I-33 (0.115 mmol, 41 mg), 4-A A solution of oxy-2-butynoic acid (0.127 mmol, 10 μL) and triethylamine (0.577 mmol, 80 μL) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture. The organic layer was separated and dried using a PE filter. The organic phase was concentrated using a stream of nitrogen. The crude product was purified by flash chromatography (0-EtOAc EtOAc EtOAc (EtOAc) The title compound (3 mg) was obtained as a 4% yield of trifluoroacetic acid salt. Other salts or free bases of E-40 can be prepared by standard methods. LC-MS (method A) Rt: 3.917 min; m/z 484.2 (M+H) ⁺ , HPLC (Method C) Rt: 6.060.

Example 71-4-- [(6-amino-7-methoxy-quinolin-4-yl) oxy] - N - (4- pyridin-2-yl-ethyl) benzoyl-amine (I-34) Preparation

The title compound was prepared using the method of compound synthesis-33 I, i.e., to obtain 190 mg of 4 - [(6-amino-7-methoxy-quinolin-4-yl) oxy] - N - (4- B Pyridin-2-yl)benzamide (22% in 2 steps). LC-MS (Method A) Rt: 5.232 min; m / z 415.2 (M + H) +.

Example 72-4-- [(6-amino-7-methoxy-quinolin-4-yl) oxy] - N - (4- pyridin-2-yl-methoxy) benzoyl-amine (I-35 Preparation

The title compound was prepared using the method of compound synthesis-33 I, i.e., to obtain 60 mg of 4 - [(6-amino-7-methoxy-quinolin-4-yl) oxy] - N - (4- methyl Oxypyridin-2-yl)benzamide (13% in 2 steps). LC-MS (Method A) Rt: 4.611 min; m / z 209.1 ((M + H) / 2) +.

Example 73 - Preparation of BTK Inhibitor

The following compounds were synthesized following the methods described for the preparation of compounds E-1 to E-40. Salts can be converted to the corresponding free base or other salts by standard reaction.

Examples 74-4-- ((6-amino-7- (2- (piperidin-1-yl) ethoxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzene Formamide (I-36)

4 - ((6-nitro-7- (2- (piperidin-1-yl) ethoxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzoyl amine Preparation. Add 2-(N-piperidinyl)ethanol (390 mg, 37.3 mmol, 1 eq.) and triphenylphosphine (1.3 g, 49 mmol, 2 eq.) to compound I-15 (1.0) Gram, 24 mmol, 1 eq. in tetrahydrofuran (12 mL). DIAD (0.9 mL, 49 mmol, 2 eq.) was added at 0 ° C and the mixture was stirred at 0 ° C for 2 hr. After completion, the reaction mixture was concentrated under reduced pressure and diluted with dichloromethane m. The organic layer was dried over sodium sulfate and concentrated to give a crude residue, which was purified by silica gel chromatography (8% methanol in dichloromethane). - nitro-7- (2- (piperidin-1-yl) ethoxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzoyl-amine (1.1 g, 74.3 %). ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm) = 10.89 (s, 1H), 8.82 (d, 1H, J = 5.2Hz), 8.78 (s, 1H), 8.40 (d, 1H , J = 4.0 Hz), 8.20 (dd, 3H, J = 3.6, 8.6 Hz), 7.86 (m, 1H), 7.80 (s, 1H), 7.45 (d, 2H, J = 8.6 Hz), 7.27 (m) , 3H), 6.72 (d, 1H, J = 5.2 Hz), 4.4 (m, 2H), 2.78 (d, 2H, J = 2.36 Hz), 2.33 (4H, m), 1.36 (m, 6H).

4 - ((6-amino-7- (2- (piperidin-1-yl) ethoxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzoyl amine Preparation. Iron powder (2.4 g, 42.9 mmol, 20 equivalents) and concentrated hydrochloric acid (1.79 mL, 10 equivalents) were added to 4-((6-nitro-7-(2-(piperidin-1-yl)) oxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzoyl-amine (1.1 g, 2 mmol, 1 eq) of the ethanol suspension. The reaction mixture was heated at 50 °C for 2 hours. After completion, the reaction was filtered through celite and washed with 10% methanol in dichloromethane. The organic layer is basified with aqueous ammonia, dried over sodium sulfate, and then concentrated to give a crude residue which is purified by silica gel chromatography (10% methanol in dichloromethane). The title compound (370 mg, 26.4%). ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm) = 10.89 (s, 1H), 8.82 (d, 2H, J = 4.96Hz), 8.18 (d, 1H, J = 8.52Hz), 8.13 (d, 2H, J = 8.6 Hz), 7.83 (m, 1H), 7.32 (s, 1H), 7.18 (m, 3H), 7.09 (s, 1H), 6.72 (d, 1H, J = 3.3 Hz) ), 5.48 (m, 2H), 4.23 (m, 2H), 2.84 (m, 4H), 1.66 (m, 6H).

Examples 75-4-- ((6- (but-2-yn-acyl) -7- (2- (piperidin-1-yl) ethoxy) quinolin-4-yl) oxy) - N - Preparation of (pyridin-2-yl)benzamide (E-95)

EDC.HCl (139 mg, 0.731 mmol, 1.5 eq.) and 2-butynoic acid (36 mg, 0.428 mmol, 2.5 eq.) were added to compound I-36 (150 mg, 0.292 mmol) at 0 °C. Ear, 1 equivalent) in pyridine (6 mL). The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 2 hours. After completion, the reaction was poured into ice water and extracted with 10% methanol dichloromethane. The organic layer was dried over sodium sulfate and evaporated to dryness crystals crystals crystals , 15%). ^{1 H NMR (400MHz, DMSO-} D 6, 300K): δ (ppm) 10.85 (s, 1H), 9.76 (s, 1H), 8.76 (s, 1H), 8.62 (d, 1H, J = 5.0Hz) , 8.19 (m, 3H), 7.85 (t, 1H, J = 8.0 Hz), 7.60 (s, 1H), 7.36 (d, 2H, J = 8.5 Hz), 7.18 (m, 1H), 6.66 (d, 1H, J=5.0 Hz), 4.36 (t, 2H, J = 5.8 Hz), 2.76 (m, 2H), 2.49 (m, 4H), 2.06 (s, 3H), 1.54 (m, 4H), 1.35 ( m, 2H

Examples 76-4-- ((6-amino-7- (2- (1-pyrrolidinyl) ethoxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzoate Preparation of guanamine (I-37)

4 - Preparation of benzoyl amine (pyridin-2-yl) - ((6-nitro-7- (2-bromoethoxy) quinolin-4-yl) oxy) - N. 2-Bromoethanol (0.26 mL, 37.3 mmol, 1 eq.) and triphenylphosphine (1.95 g, 74.6 mmol, 2 eq.) were added to I-15 (1.5 g, 37.3 mmol) at room temperature. 1 equivalent) in tetrahydrofuran (20 ml). DIAD (1.46 mL, 74.6 mmol, 2 eq.) was added at 0 ° C, and the mixture was stirred at room temperature for 1 hour and at room temperature for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give a crude orange compound 4 - ((6-nitro-7- (2-bromoethoxy) quinolin-4-yl) oxy) - N - (pyridin- 2-yl)benzamide (6.0 g crude).

4 - ((6-nitro-7- (2- (1-pyrrolidinyl) ethoxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) amine of benzoyl preparation. Potassium carbonate (4.89 g, 35.4 mmol, 3 eq) was added to 4 - ((6-nitro-7- (2-bromoethoxy) quinolin-4-yl) oxy) - N - ( Pyridin-2-yl)benzamide (6.0 g, 11.8 mmol, 1 eq.) in N,N-dimethylformamide (50 mL). Pyrrolidine (1.07 ml, 12.9 mmol, 1.1 equivalent) was added and the reaction mixture was heated at 100 °C for 2 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give a crude mass, which was purified by column chromatography (mite: 100-200; elution: 5% methanol in dichloromethane). pure 4 - ((6-nitro-7- (2- (1-pyrrolidinyl) ethoxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzoyl amine (1.4 g, 80%) yellow solid compound.

4 - ((6-amino-7- (2- (1-pyrrolidinyl) ethoxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) amine of benzoyl preparation. Iron powder (3.08 g, 56.1 mmol, 20 equivalents) and concentrated hydrochloric acid (2.5 ml, 28.0 mmol, 10 equivalents) were added to 4-((6-nitro-7-(2-) pyrrolidin-1- yl) ethoxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzoyl-amine (1.4 g, 2.8 mmol, 1 eq.) of ethanol (10 ML) solution. The reaction mixture was heated at 50 °C for 2 hours. After completion, the reaction mixture was filtered through celite and washed with 10% methanol in dichloromethane and ammonia. The layers are separated, and the reaction mixture is concentrated to give a crude compound which is purified by column chromatography (mite: 100-200; elution: 10% methanol in dichloromethane) to obtain the desired yellow solid. compound 4 - ((6-amino-7- (2- (1-pyrrolidinyl) ethoxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzoyl Amine (650 mg, 50%).

Example 77-4-- [[6- (acyl-2-ynyl) -7- [2- (1-pyrrolidinyl) ethoxy] quinolin-4-yl] oxy] - N - Preparation of (2-pyridyl)benzamide (E-98)

2-butynoic acid (53 mg, 0.6 mmol, 1.5 eq.) and EDC.HCl (202 mg, 1.06 mmol, 2.5 eq.) were added to compound I-37 (200 mg, 0.4 mmol) at 0 °C. Ear, 1 equivalent) in pyridine (5 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with ice water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by column chromatography (yield: 230-400; elution: 10% methanol in dichloromethane) The title compound (58 mg, 25.4%) was obtained as pale yellow solid. LC-MS (method B) Rt: 4.67 min; m/z 524.5 (M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-D ₆ , 300K): δ (ppm) = 10.86 (1H, s), 9.97 (1H, s), 8.76 (1H, s), 8.63 (1H, d, J = 5.2 Hz), 8.40 (1H, d, J = 4.4 Hz), 8.20-8.17 (3H, m), 7.87-7.83 ( 1H, m), 7.60 (1H, s), 7.38 (2H, d, J = 8.8 Hz), 7.19-7.16 (1H, m), 6.66-6.65 (1H, m), 4.37-4.34 (2H, m) , 2.90-2.87 (2H, m), 2.60 (4H, s), 2.06 (3H, s), 1.74 (4H, s)

Example 78 - Preparation of BTK Inhibitor

The following compounds were synthesized following the procedures described in Preparation Examples E-95 and E-98.

Example 79-4-((6-Amino-7-(2-hydroxyethoxy)quinolin-4-yl)oxy)-N-(pyridin-2-yl)benzamide (I-38) Preparation

4 - ((6-nitro-7- (2- (tetrahydro -2 H - pyran-2-yloxy) ethoxy) quinolin-4-yl) oxy) - N - (pyridin - Preparation of 2-yl)benzamide. Compound I-15 (1.6 g, 3.9 mmol), 2-(tetrahydro- 2H -pentan-2-yloxy)ethanol (0.672 g, 4.6 mmol) and triphenylphosphine (2.5 g) The mixture was placed in tetrahydrofuran (20 ml), cooled to 0 ° C, DIAD (1.5 mL, 7.8 mmol) was added dropwise and the mixture was stirred at the same temperature for one hour. The reaction mixture is concentrated to obtain a crude product, which is further purified by column chromatography using phthalocyanine (100-200 mesh) and 0-2% methanol in dichloromethane to obtain a brown viscous solid. - ((6-nitro-7- (2- (tetrahydro -2 H - pyran-2-yloxy) ethoxy) quinolin-4-yl) oxy) - N - (pyridin-2 -yl)benzamide (1.8 g, 90%).

4 - ((6-amino-7- (2-hydroxyethoxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) amine of the benzoyl. 4 - ((6-nitro-7- (2- (tetrahydro -2 H - pyran-2-yloxy) ethoxy) quinolin-4-yl) oxy) - N - (pyridin- 2-yl)benzamide (1.8 g, 3.3 mol) in ethanol (20 ml), iron powder (3.6 g, 66.0 mmol) and concentrated hydrochloric acid (3.0 mL, 33.0 mmol) After the addition, the reaction mixture was heated at 50 ° C for 1 hour. The reaction mixture was diluted with ethyl acetate, basified with aqueous ammonium hydroxide and washed with water. The organic portion was dried over sodium sulfate, filtered and concentrated to give a crude material, which was further purified by column chromatography using hexane (100-200 mesh) and 0-5% methanol in dichloromethane. to obtain a pale brown solid form of 4 - ((6-amino-7- (2-hydroxyethoxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzoyl amine (1.2 grams, 85.7%).

Example 80-4-- [[6- (acyl-2-ynyl) -7- (2-hydroxyethoxy) quinolin-4-yl] oxy] - N - (pyridin-2-yl Preparation of benzoguanamine (E-110)

EDC.HCl (0.230 g, 1.2 mmol) and 2-butynoic acid (0.060 g, 0.72 mmol) were added to compound I-38 (0.200 g, 0.48 mmol) of pyridine at 0 °C. The solution was stirred at room temperature for 2 hours. Water was added and extracted with ethyl acetate. The organic portion was dried over sodium sulphate, filtered and concentrated to give a crude material, which was taken in tetrahydrofuran: water (1:1) (5 ml), lithium hydroxide monohydrate (LiOH ^. H ₂ O, 4 equivalents) were added and the reaction mixture was stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. The organic portion was dried over sodium sulfate, filtered and concentrated to give a crude material, which was further purified by column chromatography using hexane (100-200 mesh) and 0-3% methanol in dichloromethane. The title compound (0.040 g, 18.1%) was obtained. LC-MS (Method B) Rt: 5.20 min; m / z 483.2 (M + H) +; 1 H NMR (400MHz, DMSO-D 6): δ (ppm) = 10.85 (s, 1H), 9.94 (s , 1H), 8.94 (s, 1H), 8.60 (d, 1H, J = 5.12 Hz), 8.40 (d, 1H, J = 4.0 Hz), 8.20-8.17 (m, 3H), 7.87-7.83 (m, 1H), 7.49-7.47 (m, 1H), 7.37-7.35 (m, 2H), 7.19-7.16 (m, 1H), 6.64 (d, 1H, J = 5.0 Hz), 5.28-5.25 (t, 1H) , 4.23-4.22 (m, 2H), 3.86-3.85 (t, 2H) and 2.50 (s, 3H). HPLC (method D) Rt: 5.197.

Example 81 - Preparation of BTK Inhibitor

The following compounds are essentially synthesized according to the procedure described for the preparation of compound E-110 using a TLP or TBDMS protected glycol or a dialkyl acetal protected triol.

Example 82-4-{[(6-(2-{ Preparation benzoyl amine (I-39) of (pyridin-2-yl) --4-yl} ethyl) amino) quinolin-4-yl] oxy} - N

Compound I-18 (1.0 g, 2.8 mmol) and Phenyl-4-ylacetaldehyde hydrochloride (1.3 g, 8.4 mmol) was placed in ethanol (15 mL) and the mixture was stirred for 30 min. Thereafter, sodium cyanoborohydride (NaCNBH3, 0.879 g, 14.0 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was concentrated, water was added, and then extracted with 10% methanol in dichloromethane. The organic portion was dried over sodium sulfate, filtered and concentrated to give a crude material, which was further purified by column chromatography using silica gel (100-200 mesh) and 0-4% methanol in dichloromethane. This gave a yellow solid I-39 (0.700 g, 53.8%).

Example 83-4-{[6-(propylene fluorenyl (2-{ Preparation of phenyl-4-yl}ethyl)amino)quinolin-4-yl]oxy- N- (pyridin-2-yl)benzamide (E-117)

Add triethylamine (NEt ₃ , 0.3 mL, 2.1 mmol) and propylene oxime chloride (0.13 mL, 1.68 mmol) to I-39 (0.200 g, 0.42 mmol) of dichloromethane at 0 °. The solution was stirred at room temperature for 12 hours (6 mL). Water was added and extracted with dichloromethane. The organic portion was dried over sodium sulphate, filtered and concentrated to give a crude material, which was taken in tetrahydrofuran: water (1:1) (5 ml), lithium hydroxide monohydrate (LiOH ^. H ₂ O, 4 equivalents) were added and the reaction mixture was stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. The organic portion was dried over sodium sulfate, filtered and concentrated to give a crude material, which was further purified by column chromatography using silica gel (100-200 mesh) and 0-4% methanol in dichloromethane. The title compound (0.060 g, 27.2%) was obtained as pale yellow solid. LC-MS (Method B) Rt: 4.90 min; m / z 524.4 (M + H) +; 1 H NMR (400MHz, DMSO-D6): δ (ppm) = 10.87 (s, 1H), 8.81-8.80 ( m,1H), 8.45-8.40 (m,1H), 8.25-8.15 (m,5H), 7.89-7.82 (m,1H), 7.81-7.75 (m,1H), 7.75-7.42 (m,2H), 7.20-7.15 (m, 1H), 6.90-6.83 (m, 1H), 6.22-6.20 (m, 1H), 6.10-6.09 (m, 1H), 5.58-5.56 (m, 1H), 3.93-3.91 (m , 2H), 3.45-3.42 (m, 4H), 2.44-2.41 (m, 2H) and 2.30-2.29 (m, 4H). HPLC (method D) Rt: 4.985.

Example 84-4-{[6-(but-2-ynyl) (2-{ Preparation benzoyl amine (E-118) of (pyridin-2-yl) - 4-yl} ethyl) amino) quinolin-4-yl] oxy} - N

This compound was prepared in a manner similar to that described for the preparation of compound E-117 using compound 1-39 and 2-butynoic acid. LC-MS (Method B) Rt: 6.90 min; m / z 536.45 (M + H) +.

Examples 85-4-- {[(6- (3- {dimethylamino} propyl) amino) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine ( Preparation of I-40)

4 - [(6-iodo-quinolin-4-yl) oxy] - N - (pyridin-2-yl) amine of the benzoyl. Cesium carbonate (Cs ₂ CO ₃ , 9.7 g, 29.8 mmol) and 4-chloro-6-iodo-quinoline (5.1 g, 17.8 mmol) were added to compound I-1 (3.2 g, 14.9 mmol) The reaction mixture was heated at 120 ° C for 12 hours in a solution of N,N-dimethylformamide (40 mL). Water was added and extracted with ethyl acetate. The organic portion was dried over sodium sulfate, filtered and concentrated to give a crude material, which was further purified by column chromatography using hexane (100-200 mesh) and 0-80% ethyl acetate in hexanes. , i.e. a brown solid form of 4 - [(6-iodo-quinolin-4-yl) oxy] - N - (pyridin-2-yl) benzoyl-amine (5.0 g, 74.6 mmol).

4 - {[(6- (3- {dimethylamino} propyl) amino) quinolin-4-yl] oxy} - N - (pyridin-2-yl) amine of the benzoyl. 4 - [(6-iodo-quinolin-4-yl) oxy] - N - (pyridin-2-yl) benzoyl-amine (1.0 g, 2.1 mmol), N, N - dimethyl-propionic - 1,3-diamine (0.857 g, 8.4 mmol) and cesium carbonate (Cs ₂ CO ₃ , 1.3 g, 4.2 mmol) in toluene (12 mL), then the reaction mixture was taken from nitrogen Gas for 10 minutes. Then Pd ₂ (dba) ₃ (0.096 g, 0.105 mmol) and Xanthphos (0.121 g, 0.210 mmol) were added, and the reaction mixture was heated in a microwave oven at 150 ° C for 1 hour. The reaction mixture was cooled, water was added and extracted with ethyl acetate. The organic portion was dried over sodium sulfate, filtered and concentrated to give a crude material, which was further purified by column chromatography using silica gel (100-200 mesh) and 0-10% methanolic ammonia in dichloromethane. Purification gave a solid solid I-40 (0.700 g, 74.4%).

Examples 86-4-- {[6- (2-ynyl acyl (3- {dimethylamino} propyl) amino) quinolin-4-yl] oxy} - N - (pyridin-2 Preparation of benzomethamine (E-119)

DIPEA (0.9 ml, 4.9 mmol), 2-butynoic acid (0.201 g, 2.4 mmol) and T3P (1.5 mL, 2.4 mmol) were added to I-40 (0.220 g, 0.49) at 0 °C. The reaction mixture was heated at 70 ° C for 16 hours in a solution of EtOAc (5 mL). The reaction mixture was cooled, water was added and extracted with ethyl acetate. The organic portion was dried over sodium sulphate, filtered and concentrated to give a crude material, which was taken in tetrahydrofuran: water (1:1) (5 ml), lithium hydroxide monohydrate (LiOH ^. H ₂ O, 4 equivalents) were added and the reaction mixture was stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. The organic portion was dried with EtOAc EtOAc EtOAcjjjjjjj LC-MS (method B) Rt: 3.76 min; m/z 508.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-D ₆ ): δ (ppm) = 10.80 (s, 1H), 8.81 - 8.79 (m, 1H), 8.40 (d, 1H, J = 3.96 Hz), 8.21-8.19 (m, 4H), 8.10-8.07 (m, 1H), 7.88-7.82 (m, 2H), 7.43-7.41 (m , 2H), 7.19-7.16 (m, 1H), 6.87-6.82 (m, 1H), 3.84-3.81 (m, 2H), 2.20-2.19 (m, 2H), 2.11-2.02 (m, 9H) and 1.77 -1.60 (m, 2H). HPLC (method D) Rt: 8.791.

Example 87 - Preparation of BTK Inhibitor

The following compounds were synthesized in a manner similar to that described for the preparation of compounds E-117 and E-119.

Preparation of Example 88-4-Hydroxy- N- [4-(trifluoromethyl)pyrimidin-2-yl]benzamide (I-41)

Preparation of 4-methoxy- N- [4-(trifluoromethyl)pyrimidin-2-yl]benzamide. 4-Methoxybenzylammonium chloride (3.8 ml, 28.2 mmol, 1 eq.) was added to stirred 4-(trifluoromethyl)pyrimidin-2-amine (4.6 g, 28.2 mmol). Ear, 1 equivalent) in pyridine (50 ml) solution. The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 1 hour. After completion, the reaction mixture was diluted with ethyl acetate and extracted with 1N hydrochloric acid and acid. The organic layer is dried over sodium sulfate and concentrated to give a crude compound, which is purified by column chromatography (neutral alumina; elution; 40-60% ethyl acetate in hexane) White velvet solid 4-methoxy- N- [4-(trifluoromethyl)pyrimidin-2-yl]benzamide (1.5 g, 17.9%).

Preparation of 4-hydroxy- N- [4-(trifluoromethyl)pyrimidin-2-yl]benzamide: boron tribromide (4.8 ml, 50.4 mmol, 10 equivalents) at -20 °C To a solution of 4-methoxy- N- [4-(trifluoromethyl)pyrimidin-2-yl]benzamide (1.5 g, 5.04 mmol, 1 eq.) in dichloromethane (30 mL) . The reaction mixture was heated at 45 °C for 16 hours. After completion, the reaction of the reaction mixture was quenched with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried <RTI ID=0.0>

The following compounds were prepared in a manner similar to that described in Preparation 1-41: 4-hydroxy- N- (4-methylpyrimidin-2-yl)benzamide (I-42), 4-hydroxy- N- (pyrimidin-2-yl)benzamide (I-43), N- (5-tertiary butyl-1,2- Zyrid-3-yl)-4-hydroxybenzamide (I-44).

Preparation of [4- (trifluoromethyl) pyrimidin-2-yl] benzoyl-amine (I-45) - A Example 89-4-- [(6-amino-quinolin-4-yl) oxy] - N

4 - [(6-nitro-quinolin-4-yl) oxy] - N - [4- (trifluoromethyl) pyrimidin-2-yl] benzoyl preparation of amines. Potassium carbonate (2.0 g, 14.4 mmol, 3 equivalents) was added to 4-chloro-6-nitro-quinoline (1.0 g, 4.8 mmol, 1 eq.) of N,N-dimethylform In a solution of amine (10 ml). Compound I-41 (1.08 g, 3.84 mmol, 0.8 eq.) was added and the mixture was stirred at 100 &lt;0&gt; After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give a crude crystals, which was purified by methylene chloride and pentane to afford 4-[(6-nitroquinoline-4) as pale brown solid. - yl) oxy] - N - [4- (trifluoromethyl) pyrimidin-2-yl] benzoyl-amine (1.6 g, 73.3%).

4 - [(6-amino-quinolin-4-yl) yloxy] - N - [4- (trifluoromethyl) pyrimidin-2-yl] benzoyl preparation of amines. Iron (1.45 g, 26.3 mmol, 12 eq.) Was added to 4 - [(6-nitro-quinolin-4-yl) oxy] - N - [4- (trifluoromethyl) pyrimidin-2 Benzobenzamide (1.0 g, 2.19 mmol, 1 eq.) in tetrahydrofuran. Acetic acid (5 ml) was added and the reaction mixture was heated at 80 ° C for 4 h. After completion, the reaction mixture was filtered through celite and washed with ethyl acetate. The organic layer was basified with saturated sodium bicarbonate solution. The layers were dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI><RTIgt;

Example 90-4-- [(6 - ((4-methoxy-2-yn-acyl) amino) quinolin-4-yl) oxy] - N - [4- (trifluoromethyl) pyrimidine Preparation of 2-yl]benzamide (E-124)

4-methoxybut-2-ynoic acid (64 mg, 0.56 mmol, 1.2 eq.), EDC.HCl (107 mg, 0.56 mmol, 1.2 eq.) and pyridine (0.1 mL, 1.17) To a solution of compound 1-45 (200 mg, 0.47 mmol, 1 eq.) in THF (5 mL). The reaction mixture was heated at 70 ° C for 16 hours. After completion, the reaction mixture was cooled to room temperature, diluted with water and ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness crystals crystalssssssssssssssssssssssssss ). LC-MS (method B) Rt: 5.19 min; m/z 522.1 (M+H)+; ¹ H NMR (400 MHz, DMSO-D ₆ ): δ (ppm)=11.55 (1H, s), 11.20 (1H) , s), 9.10 (1H, d, J = 5.0 Hz), 8.69-8.68 (2H, m), 8.13 (2H, d, J = 8.6 Hz), 8.04 (1H, d, J = 9.1 Hz), 7.95 -7.92 (1H, m), 7.74 (1H, d, J = 4.92 Hz), 7.39 (2H, d, J = 8.72 Hz), 6.80 (1H, d, J = 5.08 Hz), 4.36 (2H, s) , 3.09 (3H, s). HPLC (method D) Rt: 7.987.

Example 91 - Preparation of BTK Inhibitor

The following compounds were synthesized following a procedure similar to that described for the preparation of compound E-124:

Preparation of (pyridin-2-yl) pyridine-2-acyl-amine (I-46) - A Example 92-5-- [(6-amino-quinolin-4-yl) oxy] - N

Preparation of methyl 5-[(6-nitroquinolin-4-yl)oxy]pyridine-2-carboxylate. Thionium chloride (49 ml, 683 mmoles, 5 equivalents) was added to 5-hydroxypyridine-2-carboxylic acid (19.0 g, 137 mmol, 1 eq.) in methanol (200 mL). ) in suspension. The reaction mixture was heated at reflux for 24 hours. After completion, the reaction mixture is reacted with saturated sodium bicarbonate solution. The mixture was stopped and extracted with ethyl acetate. The organic layer was dried <RTI ID=0.0></RTI> to <RTI ID=0.0> Barium carbonate (45 grams, 137 millimolar, 3 equivalents), 4-chloro-6-nitro-quinoline (9.5 grams, 45.8 millimoles, 1 equivalent) and copper (288 mg, 4.58 millimolar, 0.1 equivalent) was added to a solution of methyl 5-hydroxypyridine-2-carboxylate (7.0 g, 45.8 mmol, 1 eq.) in N,N-dimethylformamide (100 mL). The reaction mixture was heated in a microwave oven at 100 ° C for 45 minutes. After completion, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give a crude compound, which was purified by column chromatography (e.g.: 100-200; elution: 2% methanol in dichloromethane). Methyl 5-[(6-nitroquinolin-4-yl)oxy]pyridine-2-carboxylate (7.5 g, 50%).

5 - [(6-nitro-quinolin-4-yl) oxy] - N - (pyridin-2-yl) pyridine-2-carboxylic Amides of. Trimethylaluminum (11.5 ml, 23 mmol, 5 eq.) was added to a solution of 2-aminopyridine (650 mg, 6.9 mmol, 1.5 eq.) in toluene (30 mL). The reaction mixture was stirred at the same temperature for 10 minutes. 5-[(6-Nitroquinolin-4-yl)oxy]pyridine-2-carboxylate (1.5 g, 4.6 mmol, 1 eq.) was added at 0 ° C and the reaction mixture was taken at 70 ° C Heat for 16 hours. After completion, the reaction mixture was passed through a bed of celite and washed with ethyl acetate. The filtrate was washed with water and concentrated to give a crude compound, which was purified by column chromatography (yield: 100-200; elution: 1% methanol in dichloromethane) to give an off-white solid. 5 - [(6-nitro-quinolin-4-yl) oxy] - N - (pyridin-2-yl) pyridine-2-acyl-amine (1.3 g, 73%).

5 - [(6-amino-quinolin-4-yl) oxy] - N - (pyridin-2-yl) pyridin-2-carboxylic Amides of. Under a hydrogen atmosphere Pd / C (400 mg) was added to 5 - [(6-nitro-quinolin-4-yl) oxy] - N - (pyridin-2-yl) pyridine-2-acyl-amine ( 1.3 g, 3.36 mmol, 1 eq. of dichloromethane in methanol (15 mL; 15 mL). The reaction mixture was stirred at room temperature for 24 hours. After completion, the reaction mixture was filtered through celite and washed with dichloromethane: methanol. The filtrate was concentrated and purified by column chromatography (mite: 100-200; elution: 5% methanol in dichloromethane) to give a pale yellow solid I-46 (1.1 g, 91%) ).

Preparation of pyridine (pyridin-2-yl) -2-Amides (E-135) - A Example 93-5-- {[6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy} - N

Add triethylamine (0.4 mL, 2.7 mmol, 5 eq.) to mp. N-dimethylformamide (1 ml) in solution. The reaction mixture was stirred at the same temperature for 2 minutes. Propylene hydrazine chloride (0.04 ml, 0.8 mmol, 1.5 eq.) was added at 0 ° C and the mixture was stirred at the same temperature for 30 min. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give a crude mass, which was purified by column chromatography (mite: 100-200; elution: 1% methanol in dichloromethane). The title compound was obtained as a pale yellow solid (30 mg, 14%). LC-MS (method B) Rt: 5.20 min; m/z 412.3 (M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-D ₆ ): δ (ppm) = 10.58 (1H, s), 10.35 (1H) , s), 8.78 (1H, s), 8.69 (1H, s), 8.41 (1H, d, J = 4.4 Hz)), 8.32-8.27 (2H, m), 8.06 (1H, s), 8.01 (2H) , d, J = 7.2 Hz), 7.92 (1H, s), 7.23 (1H, s), 6.96 (1H, s), 6.48 (2H, d, J = 9.6 Hz), 6.33 (1H, d, J = 16.8 Hz), 5.80 (1H, s). HPLC Rt: 5.142.

Example 94 - Preparation of a BTK Inhibitor

The following compounds were synthesized following a procedure similar to that described for the preparation of compound E-135:

Preparation of (4-methyl-pyridin-2-yl) pyridine-3-acyl-amine (I-47) - A Example 95-6-- [(6-amino-quinolin-4-yl) oxy] - N

Preparation of 6-[(6-nitroquinolin-4-yl)oxy]pyridine-3-carboxylic acid. Potassium carbonate (7.9 g, 57.8 mmol, 2 eq.) was added to 4-hydroxy-6-nitro-quinoline (5.5 g, 28.9 mmol, 1 eq.) of N,N-dimethylform. Amine (50 ml) in solution. Ethyl 6-chloropyridine-3-carboxylate (8.0 g, 43.3 mmol, 1.2 eq.) was added and the mixture was stirred at 100 ° C for 2 hr. After completion, the reaction mixture is diluted with water and then Extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give a crude solid, which was purified eluting with methylene chloride and pentane to afford pure 6-[(6-nitroquinolin-4-yl)oxy] Ethyl pyridine-3-carboxylate (5.5 g, 59.1%) was obtained as a pale yellow solid. Add lithium hydroxide (1.2 g, 29.4 mmol, 2 eq.) to ethyl 6-[(6-nitroquinolin-4-yl)oxy]pyridine-3-carboxylate (5.0 g, 14.7 m Moore, 1 eq.) of tetrahydrofuran:methanol (5:3:2) (40 mL). After completion, the reaction mixture was concentrated; water was added and then neutralized with concentrated hydrochloric acid. The obtained solid was filtered, washed with water and diethyl ether, and then dried to give 6-[(6-nitroquinolin-4-yl)oxy]pyridine-3-carboxylic acid as a pale green solid (4.0 Grams, 88.8%).

Preparation of N- (4-methylpyridin-2-yl)-6-[(6-nitroquinolin-4-yl)oxy]pyridine-3-carboxamide. CMPI (1.2 g, 4.8 mmol, 1.5 equivalents) and DIPEA (1.7 mL, 9.6 mmol, 3 equivalents) were added to 6-[(6-nitroquinolin-4-yl)oxy]pyridine- 3-carboxylic acid (1.0 g, 3.2 mmol, 1 eq.) and 4-methylpyridin-2-amine (378 mg, 3.5 mmol, 1.1 eq.) in acetonitrile (15 mL). The reaction mixture was heated at 80 ° C for 16 hours. After completion, the reaction mixture was cooled and water was added. The obtained solid was filtered off and washed with diethyl ether to give N- (4-methylpyridin-2-yl)-6-[(6-nitroquinolin-4-yl)oxy Pyridyl-3-carboxamide (800 mg, 66.6%).

6 - [(6-amino-quinolin-4-yl) oxy] - N - (4- methyl-pyridin-2-yl) pyridine-3-carboxylic Amides of. Iron powder (1.0 g, 19 mmol, 10 equivalents) and ammonium chloride (1.0 g, 19 mmol, 10 equivalents) were added to N- (4-methylpyridin-2-yl)-6-[ (6-Nitroquinolin-4-yl)oxy]pyridine-3-carboxamide (800 mg, 1.9 mmol, 1 eq.) in ethanol: water (1:1) (20 mL). The reaction mixture was heated at 80 ° C for 16 hours. After completion, the reaction mixture was filtered through a celite bed and washed with ethanol. The filtrate was concentrated to give a crude mass which was diluted with water and then extracted with 25% isopropyl alcohol chloroform. The organic layer was dried <RTI ID=0.0>

Examples 96-6-- {[6- (4-methoxy-2-yn-acyl amino) quinolin-4-yl] oxy} - N - (4- methyl-pyridin-2-yl) pyridine Preparation of 3-methylformamide (E-143)

DIPEA (0.97 ml, 1.59 mmol, 10 equivalents), 4-methoxybut-2-ynoic acid (120 mg, 1.06 mmol, 2 eq.) and T3P (1.0 mL, 1.59 mmol) at 0 °C To the solution of the compound I-47 (200 mg, 0.53 mmol, 1 eq.) in THF (4 mL). The reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried with EtOAc EtOAc EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH LC-MS (Method B) Rt: 4.67 min; m/z 46 </RTI> (M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-D6): δ (ppm) = 11.17 (1H, s), 11.05 (1H, s), 9.24 (1H, s), 8.65 (1H, d, J = 7.6 Hz), 8.53 (1H, s), 8.28 (1H, d, J = 4.8 Hz), 8.15-8.13 (1H, m), 8.09 (1H, s), 7.89 (1H, m), 7.81 (1H, d, J = 9.2 Hz), 7.36 (1H, d, J = 8.8 Hz), 7.06 (1H, d, J = 4.4 Hz), 6.22 (1H, d, J = 7.2 Hz), 4.35 (2H, s), 3.34 (3H, s), 2.49 (3H, s). HPLC Rt: 4.085.

Example 97 - Preparation of BTK Inhibitor

The following compounds were synthesized following a procedure similar to that described for the preparation of compound E-143.

Example 98-4-(2,3-Dihydro-1 H -[1,4] Preparation of (pyridin-2-yl) benzoyl amine (I-48) of the - and [3,2- g] quinolin-9-yloxy) - N

4 - [(6-amino-7-hydroxy-quinolin-4-yl) oxy] - N - (pyridin-2-yl) amine of the benzoyl. Iron powder (11.1 g, 199.0 mmol) and concentrated hydrochloric acid (9.0 ml, 99.5 mmol) were added to a solution of compound I-15 (4.0 g, 9.95 mmol) in ethanol (60 ml). The reaction mixture was stirred at room temperature. The reaction mixture was poured into ice water, basified with sodium bicarbonate and ethyl acetate. The organic portion was dried over sodium sulfate, filtered and concentrated to give 4-[(6-amino-7-hydroxyquinolin-4-yl)oxy] -N- (pyridine-2) as a pale green solid. -yl)benzamide (2.0 g, 54%).

4-(2,3-dihydro-1 H -[1,4] And [3,2-g] quinolin-9-yloxy) - N - benzoyl Preparation of amine (pyridin-2-yl): Potassium carbonate (1.3 g, 9.6 mmol) was added to 4- [(6-amino-7-hydroxy-quinolin-4-yl) oxy] - N - (pyridin-2-yl) benzoyl-amine (1.2 g, 3.2 mmol) and 1,2-dibromo - ethane (0.96 mL, 10.6 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture was cooled, water was added and extracted with ethyl acetate. The organic portion was dried over sodium sulfate, filtered and concentrated to give a crude material, which was further purified by column chromatography using hexane (100-200 mesh) and 0-40% ethyl acetate in hexanes. Purification gave a pale yellow solid I-48 (0.500 g, 41%).

Example 99-4-[(1-(but-2-ynindolyl)-2,3-dihydro-1 H -[1,4] Preparation of (pyridin-2-yl) benzoyl amine (E-147) of the - and [3,2- g] quinolin-9-yl) oxy] - N

A solution of compound I-48 (0.100 g, 0.25 mmol) and ethyl buty-2-ynoate (0.084 g, 0.75 mmol) in tetrahydrofuran (5 mL) was cooled at 0 ° C. 0.6 ml, 1.2 mmol was added dropwise, and the reaction mixture was heated at 80 ° C for 5 hours. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with a chloroform solution of 25% isopropyl alcohol. The organic portion was dried over sodium sulfate, filtered and concentrated to give a crude material, which was further purified by column chromatography using hexane (100-200 mesh) and 0-3% methanol in dichloromethane. The title compound (0.030 g, 25%) was obtained as pale yellow solid. LC-MS (Method B) Rt: 5.42 min; m/z 465.4 (M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-D ₆ ): δ (ppm) = 10.86 (s, 1H), 9.15 (s) , 1H), 8.62 (d, 1H, J = 5.0 Hz), 8.39 (d, 1H, J = 3.72 Hz), 8.20-8.17 (m, 3H), 7.87-7.83 (m, 1H), 7.47 (s, 1H), 7.36 (d, 2H, J = 8.60 Hz), 7.19-7.16 (m, 1H), 6.62 (d, 1H, J = 4.52 Hz), 4.46 (s, 2H), 4.30 (s, 2H) and 2.12(s,3H).

Example 100-4-[(1-(4-Methoxybut-2-ynindolyl)-2,3-dihydro-1 H -[1,4] Preparation benzoyl amine (E-148) of (pyridin-2-yl) - and [3,2-g] quinolin-9-yl) oxy] - N

This title compound was obtained from the title compound (30 mg, 25 m. %). LC-MS (method B) Rt: 5.40 min; m/z 495.4 (M+H) ⁺ ; ¹ H NMR (400 MHz, DMSO-D ₆ ): δ (ppm) = 10.87 (s, 1H), 9.18 (s) , 1H), 8.63 (d, 1H, J = 5.0 Hz), 8.39 (d, 1H, J = 3.4 Hz), 8.21-8.17 (m, 3H), 7.87-7.83 (m, 1H), 7.48 (s, 1H), 7.38-7.35 (m, 2H), 7.19-7.16 (m, 1H), 6.64-6.62 (m, 1H), 4.50 (s, 3H), 4.43-4.40 (m, 4H) and 3.16 (s, 2H). HPLC (method D) Rt: 6.610 minutes.

Example 101-4-{[6-(Amino) Preparation of (4-ethyl-pyridin-2-yl) benzoyl amine (I-49) - A-4-yl] oxy} - N

4-chloro-6-nitro Preparation of porphyrins. Thionium chloride (194 μl; 2.67 mmol) was added dropwise to 4-hydroxy-6-nitro Phenol (170 mg; 0.89 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and evaporated and evaporated. The organic layer was dried over sodium sulfate, filtered, and then evaporated. Porphyrin. LC-MS (Method A) Rt: 6.47 min; m / z 210.0 (M + H) +.

4-{[6-(nitro) 4-yl] oxy} - N - (4- ethyl-pyridin-2-yl) amine of the benzoyl. Compound I-4 (40 mg; 0.17 mmol) and cesium carbonate (65 mg; 0.20 mmol) were co-evaporated twice with toluene. The mixture was placed in anhydrous tetrahydrofuran (2 mL) and stirred at 60 ° C for 30 min. 4-chloro-6-nitro A solution of the morpholine (35 mg; 0.17 mmol) in dichloromethane (1 mL) was then evaporated. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% methanol in dichloromethane) to give 45 mg of 4-{[6-(nitro) Polin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benzamide (64%). LC-MS (Method A) Rt: 7.01 min; m / z 416.2 (M + H) +.

4-{[6-(amino) 4-yl] oxy} - N - (4- ethyl-pyridin-2-yl) amine of the benzoyl. The title compound was synthesized by the method described for the preparation of compound I-20 to give 24 mg of 4-{[6-(amino) 4-yl] oxy} - N - (4- pyridin-2-yl-ethyl) benzoyl-amine (62%). LC-MS (Method A) Rt: 5.35 min; m / z 386.2 (M + H) +.

Example 102-4-{[6-(Prodecylamino) Preparation of (4-ethyl-pyridin-2-yl) benzoyl amine (E-149) - A-4-yl] oxy} - N

The title compound was synthesized by the method described in Preparation E-20 to give 1.4 mg of 4-{[6-(propenylamino). Polin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benzamide (14%). HPLC (method C) Rt: 7.04 min; LC-MS (Method A) Rt: 6.17 min; m/z 440.2 (M+H) ⁺ .

Example 103-4-[(6-{[(2E)-4-methoxy-but-2-ynindolyl]amino} Preparation benzoyl amine (E-150) of (4-ethyl-pyridin-2-yl) - 4-yl] oxy} - N

The title compound was synthesized using the method described in Preparation E-149 to give the title compound (14%). Data: HPLC (Method C) Rt: 7.17 min; LC-MS (Method A) Rt: 6.44 min; m/z 482.2 (M+H) ⁺ .

Example 104 - Preparation of BTK Inhibitor

The following compound is substantially following the above method of synthesis: E-151: 3 - { [6- ( Bingxi Xi-ylamino) quinazolin-4-yl] amino} - N - (pyridin-2-yl) benzene A Amides; E-152: 3 - { [6- ( but-2-yn-acyl amino) quinazolin-4-yl] amino} - N - (pyridin-2-yl) benzoyl amine ; E-153: 4 - [ (6 - ((2 E) -4- methoxy-2-en-acyl amino) quinolin-4-yl) oxy] - N - (4- methoxy Pyridin-2-yl)benzamide; E-154: 4-[(6-(( 2E )-4-methoxybut-2-enylamino)quinolin-4-yl) oxy] - N - (4- methoxypyridin-2-yl) benzoyl amine; E-155: 4 - [ (6 - {[(E / Z) -4- (4- ethylpiperazin L-yl) -2-alkenyl acyl] amino} quinolin-4-yl) oxy] - N - (pyridin-2-yl) benzoyl amine; E-156: 4 - [ (6- amine quinolin-4-yl) oxy] - N - (4- propyl-pyridin-2-yl) benzoyl amine; E-157: 4 - [ [6- ( acyl-2-ynyl-amine yl) -7- [3- (1-pyrrolidinyl) propoxy] quinolin-4-yl] oxy] - N - (2- pyridyl) benzoyl amine; E-158: 4- [ [6- (Bing Xixi yl) -7- [3- (1-pyrrolidinyl) propoxy] quinolin-4-yl] oxy] - N - (2- pyridyl) benzoyl amine .

Example 105 - BTK Enzyme Activity

The BTK enzyme activity was measured using the IMAP (fluorescence polarization based on immobilized metal ion affinity) analysis outlined below.

BTK enzyme (His-BTK (Millipore catalog # 14-552)) in KR buffer (10 mM Tris-HCl, 10 mM magnesium chloride, 0.01% Tween-20, 0.05% sodium azide, 1 mM DTT, 2 mM manganese chloride, Dilute to 0.4 units/ml (U/mL) in pH 7.2).

Test compounds were serially diluted log 10 from 100 mM dimethyl hydrazine from 2 mM to 63.2 nM and then diluted 50-fold in KR buffer. The final compound concentration in the assay ranged from 10 [mu]M to 0.316 nM.

5 μl/well of test compound in KR buffer (1% final dimethylhydrazine concentration in the assay) and 5 μl/well 0.4 unit/ml BTK enzyme (final concentration in the assay is 0.1) Unit / ml) mixed. The test compound was pre-incubated with BTK enzyme for 60 minutes at room temperature, after which 5 μl/well of 200 nM labeled matrix peptide of Fluorescin in BR buffer (Blk/Lyntide matrix, eg #R7188/#R7233, Molecular Devices) Join. The final peptide matrix concentration in the assay was 50 nM. Kinase assays were initiated by the addition of 5 microliters per well of 20 μM ATP in KR buffer (final ATP concentration in BTK IMAP assay was 5 μM ATP, Km ATP). After incubation for 2 hours at room temperature, add 40 μl/well IMAP Progressive Binding Solution (according to the supplier (Molecular Devices) using 75% 1x Buffer A and 25% 1x Buffer B and 1:600 Progressive Binding Solution ) Stop the enzyme reaction. After incubation for 60 minutes in the dark room at room temperature, the FP signal was read. Fluorescence at 535 nm was measured using parallel and vertical filters to determine the difference in rotation due to the binding of the phosphorylated matrix peptide to the beads. Values were calculated as the percentage of readout (ΔmPi) of the control group containing and not containing ATP. The IC ₅₀ value was measured by curve fitting of the experimental results using Activity Base. The results are reported in Table 1.

Example 106 - EGFR Enzyme Activity

EGFR enzyme activity was measured using the IMAP (fluorescence polarization based on immobilized metal ion affinity) analysis outlined below.

EGFR enzyme (Invitrogen catalog # PR7295B) was diluted to 2.5 in KR buffer (10 mM Tris-HCl, 10 mM magnesium chloride, 0.01% Tween-20, 0.1% sodium azide, 1 mM DTT, 2 mM manganese chloride, pH 7.5). Micrograms per milliliter.

Test compounds were serially diluted log 10 from 1 mM to 31.6 nM in 100% dimethyl hydrazine. The dilution in dimethyl sulfoxide was then diluted 25-fold in KR buffer, of which 5 microliters was used in the assay, resulting in a final compound concentration ranging from 10 [mu]M to 0.316 nM in the assay.

5 μl/well of the test compound in KR buffer (1% final dimethyl sulfoxide concentration in the assay) and 5 μl/well 2.5 μg/ml EGFR enzyme (final concentration in the assay is 625) Nike / ml) mixed. Test compounds were pre-incubated with EGFR enzyme for 60 minutes at room temperature, after which 5 microliters/well of 200 nM labeled membrane peptide of Fluorescin (PDGFR-tide matrix peptide RP7084, Molecular Devices) in KR buffer was added. The final peptide matrix concentration in the assay was 50 nM. Kinase assays were initiated by the addition of 5 microliters per well of 8 μM ATP in KR buffer (final ATP concentration in EGFR IMAP assay was 2 μM, Km ATP). After incubation in the dark room for 60 minutes at room temperature, add 40 μl/well IMAP Progressive Binding Solution (according to the supplier (Molecular Devices) using 20% 1x buffer A and 80% 1x buffer B and 600x diluted beads ) Stop the enzyme reaction. After incubation for 60 minutes in the dark room at room temperature, the FP signal was read. Fluorescence at 535 nm was measured using parallel and vertical filters to determine the difference in rotation due to the binding of the phosphorylated matrix peptide to the beads. Values were calculated as the percentage of readout (ΔmPi) of the control group containing and not containing ATP. IC ₅₀ values by using GraphPad Prism6 experimental results of measured curve fitting. The results are reported in Table 1.

Claims (23)

a compound of formula I, Or a pharmaceutically acceptable salt thereof, wherein: A is CH or N, provided that if B is N, then A is CH; B is CH or N, provided that if A is N, then B is CH; T is CH Or N; U is CH or N; V is NR ₅ , O, S, SO or SO ₂ ; W is CH, N, O or S; X is C(R ₆ ), N, O or S; Y is CH , N or a bond; Z is CH or N; provided that: 0, 2, and 2 atoms of W, X, and Y are simultaneously heteroatoms; - when one of the atoms selected from W, X, and Y is O or S, Other atoms selected from W, X, Y may not be O or S; - when Y is CH or N, then X is C(R ₆ ) or N, and W is CH or N; R ₁ is H, optionally through R ₇ or C (O) R ₇ substituent of (C _1-4) alkyl, or optionally substituted by R ₇ or C (O) R substitution of the ₇ (C _1-5) alkoxy or optionally substituted by a hydroxy or (C _1-4 )alkyl substituted O-(C _2-6 )heterocycloalkyl; R ₃ is H, optionally substituted by R ₇ (C _1-3 )alkyl, or optionally R ₇ substituted by (C _3-7 )cycloalkyl; R ₄ is H, R ₁₁ C(O), R ₁₂ S(O), R ₁₃ SO ₂ , or optionally substituted by R ₁₄ (C _{1- 6} ) an alkyl group; R ₁ and R ₃ may together form a (C _2-6 )heterocycloalkyl group; R ₅ is H or (C _1-3 )alkyl; R ₂ is H, halogen, cyano, (C _1-4 ) alkyl group, (C _{2 -4} ) alkenyl, (C _2-4 )alkynyl, (C _1-3 )alkoxy, (C _3-6 )cycloalkyl; all alkyl groups of R ₂ optionally pass through one or more halogen Substituted; or R ₂ is (C _6-10 )aryl or (C _2-6 )heterocycloalkyl; R ₆ is H or (C _1-3 )alkyl; or R ₂ and R ₆ may be taken together ( C _3-7 )cycloalkenyl, or (C _2-6 )heterocyclenyl; each optionally substituted by (C _1-3 )alkyl, or one or more halogen; R ₇ is H, (C _{1 -3} ) alkoxy, or (C _2-6 )heterocycloalkyl; (one or more) hydroxyl, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl Amino, (C _3-7 )cycloalkoxy; R _{11 is} independently selected from the group consisting of: (C _1-6 )alkyl, (C _2-6 )alkenyl, and (C _{2- 6} ) alkynyl wherein each alkyl, alkenyl or alkynyl group is optionally substituted with one or more groups selected from the group consisting of hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl , (C _1-3 ) alkoxy, (C _3-7 )cycloalkoxy, optionally substituted by hydroxy, halogen, or (C _1-3 )alkoxy[(C _1-4 )alkyl ] group, optionally substituted by hydroxy, halo, or (C _1-3) alkoxy-substituted bis [(C _1-4) alkyl] amino, (C _6-10) aryl, or (C _{3- 7} ) heterocycloalkyl, or R ₁₁ is a (C _1-5 )heteroaryl group optionally substituted with one or more groups selected from a halogen or a cyano group. R ₁₂ and R _{13 are} independently selected from the group consisting of (C _2-6 )alkenyl or (C _2-6 )alkynyl, both optionally via one or more groups selected from the group consisting of Substitution: hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl]amine, (C _1-3 ) alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl, or (C _3-7 )heterocycloalkyl; or optionally one or more a (C _1-5 )heteroaryl group substituted with a group selected from halogen or cyano; R _{14 is} independently selected from the group consisting of halogen, cyano, or (C _2-6 )alkenyl or ( C _2-6 ) alkynyl, both optionally substituted by one or more groups selected from the group consisting of hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 ) alkyl]amino, bis[(C _1-4 )alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 An aryl group, a (C _1-5 )heteroaryl group or a (C _3-7 )heterocycloalkyl group. The compound according to claim 1, wherein R _{1 is} selected from the group consisting of: (C _1-7 ) alkoxy, optionally via (C _3-7 )heterocycloalkyl, (di)alkane Amine, alkoxy, or hydroxy substituted. The compound according to claim 1, wherein the ring containing W, X, and Y is selected from the group consisting of pyridyl, pyrimidinyl, and anthracene. Base, three Base, thiazolyl, Azolyl, and Azolyl. The compound according to any one of claims 1 to 3, wherein the ring containing W, X, and Y is selected from the group consisting of Group: pyridyl, pyrimidinyl, and thiazolyl. The compound according to any one of claims 1 to 3, wherein R _{2 is} selected from the group consisting of hydrogen, fluorine, chlorine, (C _1-3 ) alkyl, (C _1-3 ) alkene a (C _1-3 ) alkynyl group and a (C _1-2 ) alkoxy group; wherein the (C _1-3 ) alkyl group is optionally substituted with one or more halogens. The compound according to any one of claims 1 to 3, wherein R _{2 is} selected from the group consisting of hydrogen, fluorine, methyl, ethyl, propyl, methoxy and trifluoromethyl. The compound according to any one of claims 1 to 3 wherein R ₂ is hydrogen or (C _1-3 )alkyl; and R ₃ is hydrogen or (C _1-6 )alkyl. The compound according to any one of claims 1 to 3, wherein R _{1 is} selected from the group consisting of: (C _1-7 ) alkoxy, optionally via (di)alkylamino, alkoxy Substituting, or hydroxy, and R _{11 is} independently selected from the group consisting of: (C _1-6 )alkyl, (C _2-6 )alkenyl or (C _2-6 )alkynyl, each optionally Substituted by one or more groups selected from the group consisting of: hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, [(C _1-4 )alkyl]amino, di[( C _1-4 )alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl or (3-7C)heterocycloalkyl Or R ₁₁ is a (C _1-5 )heteroaryl group optionally substituted with one or more groups selected from halogen or cyano. The compound according to any one of claims 1 to 3, wherein R ₄ is R ₁₁ C(O), and R _{11 is} selected from the group consisting of: (C _2-6 ) alkenyl or (C) _2-6 ) alkynyl groups, each optionally substituted with one or more groups selected from the group consisting of hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, bis[(C _{1- 4} ) Alkyl]amino, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy or (C _3-7 )heterocycloalkyl. The compound according to item 1 in accordance with the scope of the patent application, which system is selected from the group consisting of: 3 - {[6- (Bingxi Xi-ylamino) quinazolin-4-yl] amino} - N - (pyridin- 2-yl) benzoyl amine; 4 - {[6- (Bingxi Xi-ylamino) quinazolin-4-yl] amino} - N - (pyridin-2-yl) benzoyl amine; 3 - {[6- (but-2-yn-acyl amino) quinazolin-4-yl] amino} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (butyl alkynyl acyl-2-ylamino) quinazolin-4-yl] amino} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (Bingxi Xi-ylamino) quinazoline 4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (2-butyn-acyl amino) quinazolin-4-yl] oxy yl} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (Bingxi Xi-ylamino) quinazolin-4-yl] oxy} - N - (4- trifluoromethanesulfonyloxy 2-yl) benzoyl amine; 4 - {[6- (2-butyn-acyl amino) quinazolin-4-yl] oxy} - N - (4- trifluoromethyl pyridin-2-yl) benzoyl amine; 4 - {[6- (acyl-2-ynyl) -7-methoxy-quinazolin-4-yl] amino} - N - (4 -(trifluoromethyl)pyridin-2-yl)benzamide; 4-{[6-(propenylamino)-7-methoxyquinazolin-4-yl]amino} -N -(pyridin-2-yl)benzamide 4 - {[6- (Bingxi Xi-ylamino) -7-methoxy-quinazolin-4-yl] amino} - N - (4- (trifluoromethyl) pyridin-2-yl) benzoate Amides; 4 - {[6- (acyl-2-ynyl) -7-methoxy-quinazolin-4-yl] amino} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6 - ((4-methoxy-2-yn-acyl) amino) quinazolin-4-yl] amino} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (Bingxi Xi-ylamino) quinazolin-4-yl] oxy} - N - (4- pyridin-2-yl-ethyl) benzoyl-amine; 4 - [(6 - (4-methoxy-2-yn-acyl) (methyl) amino quinolin-4-yl) oxy] - N - (4-methyl-pyridin-2-yl) benzoyl amine; 4-{[6-(5-( 4-yl) pent-yn-2-yl) -7-methoxy-quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - [( 6- (but-2-yn-acyl amino) quinolin-4-yl) oxy] - N - (4- ethynyl-2-yl) benzoyl amine; 4 - [(6- (D amino acyl-2-ynyl) quinolin-4-yl) oxy] - N - (4- fluoropyridin-2-yl) benzoyl amine; 4 - [(6- (Bingxi Xi-ylamino) quinolin-4-yl) oxy] - N - (4- fluoropyridin-2-yl) benzoyl amine; 4 - [(6- (Bingxi Xi-ylamino) quinolin-4-yl) oxy ] - N - (4- ethynyl-2-yl) benzoyl amine; 4 - [(6- (but-2-yn-acyl amino) quinolin-4-yl) oxy] - N - (4-propyl-pyridin-2-yl) benzoyl amine; 4 - [(6- (Bingxi Xi-ylamino) quinolin-4-yl) oxy] - N - (4- pyridin-2-propyl - yl) benzoyl amine; 4 - [(6 - ( (2 E) -4- dimethylamine-2-en-acyl amino) quinolin-4-yl) oxy] - N - ( 4-fluoro-2-yl) benzoyl amine; 4 - [(6-amino-quinolin-4-yl) oxy] - N - (4- propyl-pyridin-2-yl) benzoyl amine ; 4 - [(6 - ( (2 E) -4- dimethylamine-2-en-acyl amino) quinolin-4-yl) oxy] - N - (4- pyridin-2-propyl - yl) benzoyl amine; 4 - [(6- (prop-acyl amino) quinolin-4-yl) oxy] - N - (4- pyridin-2-yl-propyl) benzene A Amides; 4 - [(6- (Bingxi Xi-ylamino) quinolin-4-yl) oxy] - N - (4- pyridin-2-yl-methoxy) benzoyl-amine; 4- [ (6- (but-2-yn-acyl amino) quinolin-4-yl) oxy] - N - (4- pyridin-2-yl-methoxy) benzoyl-amine; 4 - [(6 ((2 E) -4- dimethylamine-2-en-acyl amino) quinolin-4-yl) oxy] - N - (4- methoxypyridin-2-yl) benzoyl amine; 4 - [(6 - ((4-methoxy-2-yn-acyl) amino) quinolin-4-yl) oxy] - N - (4- methoxy-2-yl ) benzoyl amine; 4 - [(6 - ((4-methoxy-2-yn-acyl) amino) quinolin-4-yl) oxy] - N - (4- pyridin-propyl - 2- yl) benzoyl amine; 4 - [(6 - ( (2 E) -4- methoxy-2-en-acyl amino) quinolin-4-yl) oxy] - N - ( 4-methoxypyridin-2-yl)benzamide; 4-[(6-(( 2E )-4-methoxybut-2-enylamino)quinolin-4-yl) oxy] - N - (4- pyridin-2-yl-propyl) benzoyl-amine; 4 - [(6 - ((4-methoxy-2-yn-acyl) amino) quinolin-4 - yl) oxy] - N - (4- ethynyl-2-yl) benzoyl amine; 4 - [(6 - ((4-methoxy-2-yn-acyl) amino) quinolin 4-yl) oxy] - N - (4- fluoropyridin-2-yl) benzoyl amine; 4 - [(6 - ((4-methoxy-2-yn-acyl) amino )quinoline 4-yl) oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [(6 - ((4-hydroxy-2-yn-acyl) amino) quinolin-4 yl) oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [(6 - ((4-methoxy-2-yn-acyl) amino) quinolin-4-yl ) oxy] - N - (5- ethyl-1,3-thiazol-2-yl) benzoyl amine; 4 - [(6 - ((but-2-yn-acyl amino) quinolin-4-yl ) oxy] - N - (5- ethyl-1,3-thiazol-2-yl) benzoyl amine; 5 - {[6- (4-methoxy-2-yn-acyl amino) quinoline 4-yl] oxy} - N - (pyridin-2-yl) pyridine-2-acyl-amine; 6 - {[6- (4-methoxy-2-yn-acyl amino) quinoline 4-yl] oxy} - N - (pyridin-2-yl) pyridine-3-acyl-amine; 6 - {[6- (4-methoxy-2-yn-acyl amino) quinoline 4-yl] oxy} - N - (4- methyl-pyridin-2-yl) pyridine-3-acyl-amine; 6 - {[6- (4-methoxy-2-yn-acyl amine yl) quinolin-4-yl] oxy} - N - (4- ethyl-pyridin-2-yl) pyridine-3-acyl-amine; 6 - {[6- (4-methoxy-2 alkynyl acyl group) quinolin-4-yl] oxy} - N - (pyridin-2-yl) despair 3-acyl-amine; 4 - [(6- (Bingxi Xi-ylamino) quinolin-4-yl) oxy] - N - (5- tert.butyl-1,2 Oxadiazol-3-yl) benzoyl amine; 4 - [(6- (Bingxi Xi-ylamino) quinolin-4-yl) oxy] - N - (pyrimidin-2-yl) benzoyl amine; 4 - [(6- (4-methoxy-2-yn-acyl amino) quinolin-4-yl) oxy] - N - (5- tert.butyl-1,2 Oxadiazol-3-yl) benzoyl amine; 4 - [(6- (but-2-yn-acyl amino) quinolin-4-yl) oxy] - N - (5- tert.butyl -1 ,2- Oxadiazol-3-yl) benzoyl amine; 4 - [(6-amino Bingxi Xi-yl) quinolin-4-yl] oxy} - N - (4- cyano-pyridin-2-yl) benzoyl an amine; 4 - [(6 - ((4-methoxy-2-yn-acyl) amino) quinolin-4-yl) oxy] - N - (pyrimidin-2-yl) benzoyl amine ; 4 - [(6 - ((4-methoxy-2-yn-acyl) amino) quinolin-4-yl] oxy} - N - (4- cyano-pyridin-2-yl) benzene Methionine; 4-{[6-(acryloyl) (2-{ 4-yl} ethyl) amino) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - [(6- (Bingxi Xi-ylamino) quinoline-4-yl) oxy] - N - [4- methyl-pyrimidin-2-yl] benzoyl-amine; 4 - [(6- (but-2-yn-acyl amino) quinolin-4 - yl] oxy} - N - (4- cyano-pyridin-2-yl) benzoyl amine; 4 - [(6 - ((4-methoxy-2-yn-acyl) amino) quinolin 4-yl) oxy] - N - [4- methyl-pyrimidin-2-yl] benzoyl-amine; 4 - [(6 - { [(2 E) -4- dimethylamine butyric -2 - alkenyl acyl] amino} quinolin-4-yl] oxy} - N - (4- cyano-pyridin-2-yl) benzoyl amine; 4 - ((6- (but-2-yn-XI Amino)-7-(2- Morpholino ethoxy) quinolin-4-yl) oxy) - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (2-ynyl acyl group) quinoline 4-yl] amino} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (Bingxi Xi-ylamino) quinolin-4-yl] amino} - N - ( 4-methyl-pyridin-2-yl) benzoyl amine; 4 - {[6- (2-ynyl acyl group) quinolin-4-yl] amino} - N - (4- methyl pyridin-2-yl) benzoyl amine; 4 - {[6- (Bingxi Xi-ylamino) quinolin-4-yl] amino} - N - (4- ethyl-pyridin-2-yl) benzoate Amides; 4 - {[6- (Bingxi Xi-ylamino) quinolin-4-yl] amino} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (Bing Xixi yl) -7-methoxy-quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-ethyl) benzoyl-amine; 4 - {[6- (Bing Xixi ylamine yl) -7-methoxy-quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-methoxy) benzoyl-amine; 4 - {[6- (2-ynoic acyl amino) -7-methoxy-quinolin-4-yl] amino} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6 - ((4-methoxybutyl acyl-2-ynyl) amino) quinolin-4-yl] amino} - N - (4- pyridin-2-yl-ethyl) benzoyl-amine; 4 - {[6 - ((4- oxo-2-yn-acyl) amino) -7-methoxy-quinolin-4-yl] amino} - N - (4- pyridin-2-ethyl ) Benzoyl amine; 4 - {[6- (4- ( 4-yl) but-2-yn-acyl amino) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (4 ( 4-yl) but-2-yn-acyl amino) quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-methyl) benzoyl-amine; 4 - {[6 -(5-( 4-yl) amino-pentyn-2-yl) quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-methyl) benzoyl-amine; 4 - {[6- (5-( 4-yl) amino-pentyn-2-yl) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (Bing Xixi group amino) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy } - N - (4- trifluoromethyl-pyridin-2-yl) benzoyl amine; 4 - {[6- (2-butyn-acyl amino) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (2-butyn-acyl amino) quinolin-4-yl] oxy} - N - (4- ethylpyridine 2-yl) benzoyl amine; 4 - {[6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy} - N - (4- ethyl-pyridin-2-yl) benzoyl amine; 4 - {[6- (2-butyn-acyl amino) quinolin-4-yl] oxy} - N - (4- trifluoromethyl-pyridin-2-yl) benzoyl amine; 4 - [(6 - {[ (2 E) -4- dimethylamine acyl-2-ene] amino} quinolin-4-yl] oxy} - N - (4- ethylpyridine - 2-yl)benzamide; 4-[(6-{[(2 E )-4-dimethylaminobut-2-enyl]amino}quinolin-4-yl]oxy}- N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-methyl ) benzoyl amine; 4 - {[6- (2-ynyl acyl group) quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-methyl) Benzalamine; 4-[(6-{[(2 E )-4-dimethylaminobut-2-enyl]amino}quinolin-4-yl]oxy}- N -(4 - pyridin-2-yl-methyl) benzoyl-amine; 4 - {[6- (Bingxi Xi-yl) -7-methoxy-quinolin-4-yl] oxy} - N - (pyridin-2 - yl) benzoyl amine; 4 - [(6-amino-quinolin-4-yl) oxy] - N - (4- pyridin-2-yl-ethyl) benzoyl-amine; (E) -4 -((4-(4-(4-ethylpyridin-2-yl)aminocarbamimidyl)phenoxy)quinolin-6-yl)amino) -N,N,N -trimethyl -4-Sideoxybut-2-en-1-amine oxime; 4-{[6-(propylene decylamino) 4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - [(6 - {[4-methoxy - acyl-2-ynyl] amino} quinolin 4-yl] oxy} - N - (4- pyridin-2-yl-ethyl) benzoyl-amine; 4 - [(6 - { [(2 E) -4- methoxy - butoxy -2 - alkynyl acyl] amino} quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-methyl) benzoyl-amine; 4 - [(6 - { [(2 E) - 4-methoxy-but-2-ynindolyl]amino} 4-yl] oxy} - N - (4- pyridin-2-yl-ethyl) benzoyl-amine; 5 - {[6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy } - N - (pyridin-2-yl) pyridine-2-acyl-amine; 5 - {[6- (2-ynyl acyl group) quinolin-4-yl] oxy} - N - ( Pyridin-2-yl)pyridine-2-carboxamide; 5-[(6-{[(2 E )-4-dimethylaminobut-2-enyl]amino}quinolin-4-yl ] oxy} - N - (pyridin-2-yl) pyridine-2-acyl-amine; 4 - {[6- (acyl-2-ynyl (2- {dimethylamino} ethyl) amine ) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - [(6 - { [(E / Z) -4- Morpholino-2-en acyl] amino} quinolin-4-yl) oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [(6 - { [(E) - 4- Morpholino-2-en acyl] amino} quinolin-4-yl) oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [(6 - { [(Z) - 4- Morpholino-2-en acyl] amino} quinolin-4-yl) oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - {[6 - { [(E / Z ) -4- [2-hydroxyethyl (methyl) amino] but-2-en-acyl] amino} quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoate Indoleamine; 4-{[6-{[( E )-4-[2-hydroxyethyl(methyl)amino]but-2-enyl]amino}quinolin-4-yl]oxy }- N -(pyridin-2-yl)benzamide; 4-{[6-{[( Z )-4-[2-hydroxyethyl(methyl)amino]but-2-enyl) ] amino} quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6 - { [(E / Z) -4- [2- methoxy ethyl (methyl) amino] but-2-en-acyl] amino} quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[ 6 - {[(E) -4- [2- methoxyethyl (methyl) amino] but-2-en-acyl] amino} quinolin-4-yl] oxy} - N - ( Pyridin-2-yl)benzamide; 4-{[6-{[( Z )-4-[2-methoxyethyl(methyl)amino]but-2-enyl]amino } quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6 - { [(E) -4- [2- methoxyethyl (meth yl) amino] but-2-en-acyl] amino} quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-ethyl) benzoyl-amine; 4 - {[6 -{[( E )-4-[2-methoxyethyl (methyl ) Amino] but-2-en-acyl] amino} quinolin-4-yl] oxy} - N - (4- pyridin-2-yl-methyl) benzoyl-amine; 4 - {[6- {[(E) -4- [2- methoxyethyl (methyl) amino] but-2-en-acyl] amino} quinolin-4-yl] oxy} - N - (4- Methoxypyridin-2-yl)benzamide; 4-[[7-(2-{ 4-yl} o-ethoxy) -6- (Bingxi Xi-ylamino) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - {[ 6-(4-( 4-yl) acyl-butyn-2-yl) -7-methoxy-quinolin --4- yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4- { [6-(4-( 4-yl) pent-yn-2-yl) -7-methoxy-quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[ 6-(but-2-yne fluorenyl (2-{ 4-yl} ethyl) amino) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (but-2-yn-XI yl (3- {dimethylamino} propyl) amino) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 5 - [(6 - {[( 2 E )-4-dimethylaminobut-2-enyl]]3-{ 4-yl} propyl) amino} quinolin-4-yl] oxy} - N - (pyridin-2-yl) pyridine-2-acyl-amine; 4 - {[6- (-2 butoxy -alkynyl (3-{ 4-yl} propyl) amino) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (Bing Xixi yl (3- { 4-yl} propyl) amino) quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - [(6- (but-2-yn-XI ylamino) quinolin-4-yl) oxy] - N - [4- methyl-pyrimidin-2-yl] benzoyl-amine; 4 - [(6- (2-ynyl acyl group) quinolin-4-yl) oxy] - N - [4- (trifluoromethyl) pyrimidin-2-yl] benzoyl-amine; 4 - [(6 - ((4-methoxy-2 alkynyl acyl) amino) quinolin-4-yl) oxy] - N - [4- (trifluoromethyl) pyrimidin-2-yl] benzoyl-amine; 4 - [[7- (2- methoxyethoxy) -6- (but-2-yn-acyl amino) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [(6 - (Bingxi Xi-ylamino) quinolin-4-yl) oxy] - N - [4- (trifluoromethyl) pyrimidin-2-yl] benzoyl-amine; 4 - {[6- (D - 2- alkynyl acyl amino) -7 - {[(3 R ) - tetrahydrofuran-3-yl] oxy} quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (acyl-2-ynyl) -7- (tetrahydropyran-4-yloxy) quinolin-4-yl] oxy} - N - (pyridin - 2-yl)benzamide; 4-{[6-(but-2-ynylamino)-7-{[(3 S )-tetrahydrofuran-3-yl]oxy}quinoline-4- yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6- (acyl-2-ynyl) -7- (oxetan-3-yl Oxyl) Quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (acyl-2-ynyl) -7- (3- Morpholino propoxy) quinolin-4-yl] oxy] - N - (2- pyridyl) benzoyl amine; 4 - [[6- (acyl-2-ynyl) -7- [2- (1-piperidinyl) ethoxy] quinolin-4-yl] oxy] - N - (2- pyridyl) benzoyl amine; 4 - [[6- (Bing Xixi yl amine ) -7- [2- (1-piperidinyl) ethoxy] quinolin-4-yl] oxy] - N - (2- pyridyl) benzoyl amine; 4 - {[6 - [[ (E) -4- [methyl (tetrahydro-pyran-4-yl) amino] but-2-en-acyl-yl] amino] quinolin-4-yl] oxy} - N - (pyridin-2 -yl)benzamide;4-{[6-[4-(4-ethylperidine) -1-yl)but-2-ynindolylamino]quinolin-4-yl]oxy} -N -pyridin-2-yl)benzamide; 4-[[7-(2-{ 4-yl} ethoxy) -6- (but-2-yn-acyl amino) quinolin-4-yl] oxy] - N - (4- methyl-pyridin-2-yl) benzoate Amides; 4 - [(6 - ((5-hydroxy-2-yn-acyl) amino) quinolin-4-yl) oxy] - N - (pyridin-2-yl) benzoyl amine; 4-[[6-(but-2-ynylamino)-7-(2-{ 4-yl} ethoxy) quinolin-4-yl] oxy] - N - (4- pyridin-2-yl-methoxy) benzoyl-amine; 4 - [[6- (-2 butoxy - alkynyl acyl) -7- (3- {1-piperidinyl} propoxy) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 -[[6-(but-2-ynylamino)-7-(3-(4-methylperidine) 1-yl) propoxy) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (2-ynyl acyl group -7-[2-(1-pyrrolidinyl)ethoxy]quinolin-4-yl]oxy]-N-(2-pyridyl)benzamide; 4-[[6-(propylene acyl) -7- [2- (1-pyrrolidinyl) ethoxy] quinolin-4-yl] oxy] - N - (2- pyridyl) benzoyl amine; 4 - [( 1-(but-2-yneindenyl)-2,3-dihydro-1 H -[1,4] And [3,2-g] quinolin-9-yl) oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - {[6 - [ [(E) -4- ( dimethylamino amino) but-2-en-acyl] amino] -7-methoxy-quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[6 -[4-(4-ethylperidazole 1-yl) but-2-yn-acyl amino] -7-methoxy-quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - {[ 6- (5-hydroxy-2-yn-acyl) -7-methoxy-quinolin-4-yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4- [ [6- (acyl-2-ynyl) -7-methoxy-quinolin-4-yl] oxy] - N - (4- pyridin-2-yl-methoxy) benzoyl-amine; 4-[[6-(4-( 4-yl) acyl-butyn-2-yl) -7-methoxy-quinolin-4-yl] oxy] - N - (4- methoxypyridin-2-yl) benzoyl Amine; 4-{[6-(5- Morpholino-2-yn-acyl) -7-methoxy-quinolin-4-yl] oxy} - N - (4- methoxypyridin-2-yl) benzoyl amine; 4- {[6-(but-2-ynylamino)-7-[(3 R )-1-methylpyrrolidin-3-yl]oxyquinolin-4-yl]oxy} -N - (pyridin-2-yl)benzamide; 4-{[6-(propenylamino)-7-[(3 R )-1-methylpyrrolidin-3-yl]oxyquinoline- 4- yl] oxy} - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (acyl-2-ynyl) -7- (3- (dimethylamino ) propoxy) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (Bing Xixi yl) -7- (3- ( dimethylamino) propoxy) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (2-ynyl acyl group ) -7- (2- (dimethylamino) ethoxy) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (propylene acyl) -7- (2- (dimethylamino) ethoxy) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [( 1-(4-methoxybut-2-ynindolyl)-2,3-dihydro-1 H -[1,4] And [3,2-g] quinolin-9-yl) oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (Bing Xixi yl) -7- ( 2-(4-methylperazine 1-yl) ethoxy) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (2-ynyl acyl group )-7-(2-(4-methylpiperidine) 1-yl) ethoxy) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (Bing Xixi yl) -7- (3-(4-methylperazine) 1-yl) propoxy) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (2-ynyl acyl group ) -7- (3-hydroxypropoxy) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (but-2-yn-XI ylamino) -7 - {[(2 S ) -2,3- dihydroxypropyl] oxy} quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine 4-[[6-(but-2-ynylamino)-7-{[(2 R )-2,3-dihydroxypropyl]oxy}quinolin-4-yl]oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (acyl-2-ynyl) -7- (2-hydroxyethoxy) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (Bing Xixi yl) -7- (3-hydroxypropoxy) quinolin-4-yl] oxy ]]- N- (pyridin-2-yl)benzamide; 4-[[6-(propylene decylamino)-7-{[(2 S )-2,3-dihydroxypropyl]oxy yl} quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (Bingxi Xi-ylamino) -7 - {[(2 R ) - 2,3-dihydroxypropyl] oxy} quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (Bingxi Xi-ylamino) 7- (2-hydroxyethoxy) quinolin-4-yl] oxy] - N - (pyridin-2-yl) benzoyl amine; 4 - [[6- (2-ynyl acyl Amino)-7- [3- (1-pyrrolidinyl) propoxy] quinolin-4-yl] oxy] - N - (2- pyridyl) benzoyl amine; 4 - [[6- (Bing Xixi yl amine ) -7- [3- (1-pyrrolidinyl) propoxy] quinolin-4-yl] oxy] - N - (2- pyridyl) benzoyl amine; 4 - [[6- (butyl -2-Alkynylamino)-7-(2- Morpholino-2-oxo - ethoxy) -4-quinolyl] oxy] - N - (2- pyridyl) benzoyl amine; 4 - [[6- (but-2-yn-XI Amino)-7-[2-(3-sideoxy) 4-yl) ethoxy] -4-quinolyl] oxy] - N - (2- pyridyl) benzoyl amine; and 4 - [[6- (acyl-2-ynyl-amine Base)-7-[3-(3-sideoxy 4-yl) propoxy] -4-quinolyl] oxy] - N - (2- pyridyl) benzoyl amine. a compound of formula IV, Or a pharmaceutically acceptable salt thereof, wherein: T is CH or N; U is CH or N; V is NR ₅ , O, S, SO or SO ₂ ; W is CH, N, O or S; X is C (R ₆ ), N, O or S; Y is CH, N or a bond; Z is CH or N; provided that: 0, 2, and 2 atoms of W, X, and Y are simultaneously heteroatoms; When one of the atoms of X and Y is O or S, the other atoms selected from W, X, and Y may not be O or S; - when Y is CH or N, then X is C(R ₆ ) or N, And W is CH or N; R ₁ is H, optionally substituted with R ₇ or C(O)R ₇ (C _1-4 )alkyl, or optionally substituted by R ₇ or C(O)R ₇ (C _1-5 ) alkoxy, or O-(C _2-6 )heterocycloalkyl optionally substituted by hydroxy or (C _1-4 )alkyl; R ₃ is H, optionally substituted by R ₇ a (C _1-3 )alkyl group, or a (C _3-7 )cycloalkyl group optionally substituted by R ₇ ; R ₄ is R ₁₁ C(O); R ₁ and R ₃ may be formed together (C _{2 6} ) a heterocycloalkyl group; R ₅ is H or (C _1-3 )alkyl; R ₂ is H, halogen, cyano, (C _1-4 )alkyl, (C _2-4 )alkenyl, ( C _2-4) alkynyl, (C _1-3) alkoxy, (C _3-6) cycloalkyl alkyl group; R ₂ lines of all alkyl groups optionally substituted by one or more halo; or R ₂ is ( C _6-10 ) aryl or (C _2-6 ) a cycloalkyl group; R ₆ is H or (C _1-3 )alkyl; or R ₂ and R ₆ may together form a (C _3-7 )cycloalkenyl group or a (C _2-6 )heterocyclenyl group; Optionally substituted with (C _1-3 )alkyl, or one or more halogen; R ₇ is H, (C _1-3 ) alkoxy, or (C _2-6 )heterocycloalkyl; a plurality of) hydroxy, [(C _1-4 )alkyl]amino, bis[(C _1-4 )alkyl]amino, (C _3-7 )cycloalkoxy; R _{11 is} independently selected from: (C _2-6 )alkenyl and (C _2-6 )alkynyl, alkenyl or alkynyl are each optionally substituted with one or more groups selected from the group consisting of hydroxy, (C _1-4 )alkyl, (C _3-7 )cycloalkyl, (C _1-3 )alkoxy, (C _3-7 )cycloalkoxy, (C _6-10 )aryl, (C _3-7 )heterocycloalkyl a [(C _1-4 )alkyl]amino group optionally substituted by a hydroxy group, a halogen or a (C _1-3 ) alkoxy group, or optionally a hydroxyl group, a halogen, or a (C _1-3 ) alkoxy group A substituted bis[(C _1-4 )alkyl]amino group. A compound of claim 1 or 11 for use in the treatment of Bruton's tyrosine kinase (BTK) vector disorder. A compound as claimed in claim 1 or 11 For pharmaceutical use, the agent is used to treat Bruton's tyrosine kinase (BTK) vector disorder. For example, the use of the Bruton's tyrosine kinase (BTK) vector disorder is selected from the group consisting of bladder cancer, head and neck cancer, pancreatic ductal adenocarcinoma. (PDA), pancreatic cancer, colon cancer, breast cancer, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung cancer, thymoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia , thymic cancer, brain cancer, squamous cell carcinoma, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral and oropharyngeal cancer, gastric cancer, stomach cancer, son Cervical cancer, head, neck, kidney cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immunodeficiency syndrome (AIDS)-associated lymphoma , Kaposi's sarcoma, virus-induced cancer, glioblastoma, esophageal tumor, hematological tumor, non-small cell lung cancer, chronic myeloid leukemia, diffuse large B-cell lymphoma, esophageal tumor, Central follicular lymphoma, head and neck neoplasms, hepatitis C virus infection, hepatocellular carcinoma, Hodgkin's lymphoma, metastatic colon cancer, multiple myeloma, non-Hodgkin's lymphoma (non- Hodgkin's lymphoma, primary central nervous system lymphoma, ovarian tumor, pancreatic tumor, renal cell carcinoma, small cell lung cancer, stage IV melanoma, tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, arteries Contusion, inflammatory bowel disease, dryness, eczema, scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, blood Tumor, glioma, melanoma, ulcerative colitis, atopic dermatitis, cystitis, spondylitis, uveitis, Behcets disease, rheumatic polymyalgia, giant cells Arteritis, sarcoma-like disease, Kawasaki disease, juvenile idiopathic arthritis, suppurative sweat gland inflammation, Sjögren's syndrome, dry arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's Disease, lupus, and lupus nephritis. A pharmaceutical composition for treating a hyperproliferative disorder, an inflammatory disorder, an immune disorder, or an autoimmune disorder, the pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in claim 1 or 11 or a pharmaceutically acceptable compound thereof Accept the salt. The use of claim 15 wherein the hyperproliferative disorder is selected from the group consisting of bladder cancer, head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon cancer, and breast cancer. , breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung cancer, thymoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymic cancer, brain cancer, squamous cell carcinoma, skin cancer, Eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral and oropharyngeal cancer, gastric cancer, stomach cancer, cervical cancer, head, neck, kidney cancer, kidney cancer, liver cancer, Ovarian cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immunodeficiency syndrome (AIDS)-associated lymphoma, Kaposi's sarcoma, virus-induced cancer, glia Cell tumor, esophageal tumor, hematological tumor, non-small cell lung cancer, chronic myeloid leukemia, diffuse large B-cell lymphoma, food Neoplasms, follicular center lymphoma, head and neck tumors, hepatitis C virus infection, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's lymph Non-Hodgkin's lymphoma, primary central nervous system lymphoma, ovarian tumor, pancreatic tumor, renal cell carcinoma, small cell lung cancer, and stage IV melanoma. The use of the scope of claim 15 wherein the inflammatory disorder, immune disorder, or autoimmune disorder is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, arterial atherosclerosis Sclerosing, inflammatory bowel disease, dryness, eczema, scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma and melanoma, ulcerative colitis, ectopic Dermatitis, bursitis, spondylitis, uveitis, Behcets disease, rheumatic polymyalgia, giant cell arteritis, sarcoma-like disease, Kawasaki disease, juvenile idiopathic arthritis Suppurative sweat gland inflammation, Sjögren's syndrome, dry arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's Disease, lupus, and lupus nephritis. A pharmaceutical composition for treating a solid tumor cancer, the pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or 11 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is effective inhibition Signaling between the solid tumor cancer cells and at least one microenvironment selected from the group consisting of: macrophages, mononuclear leukocytes, obese cells, helper T cells, cytotoxic T cells, regulation T cells, natural killer cells, bone marrow-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts. The use of claim 18, wherein the solid tumor cancer is selected from the group consisting of pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, and colorectal cancer. A pharmaceutical composition comprising a compound according to claim 1 or 11 and at least one pharmaceutically acceptable excipient. For example, the pharmaceutical composition of claim 20 is for the treatment of hyperplasia, inflammatory disorders, immune disorders, autoimmune disorders, or Bruton's tyrosine kinase (BTK) mediators. Sexual disorders. The pharmaceutical composition of claim 20, wherein the hyperproliferative disorder is selected from the group consisting of bladder cancer, head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon cancer, and milk lobe Breast cancer, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung cancer, thymoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymic carcinoma, brain cancer, squamous cell carcinoma, skin Cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral and oropharyngeal cancer, gastric cancer, stomach cancer, cervical cancer, head, neck, kidney cancer, kidney cancer, Liver cancer, ovarian cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immunodeficiency syndrome (AIDS)-associated lymphoma, Kaposi's sarcoma, virus-induced cancer, nerve Glioblastoma, esophageal tumor, hematological tumor, non-small cell lung cancer, chronic myeloid leukemia, diffuse large B-cell lymph Tumor, esophageal tumor, follicular center lymphoma, head and neck cancer, hepatitis C virus infection, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's disease Non-Hodgkin's lymphoma, primary central nervous system lymphoma, ovarian tumor, pancreatic tumor, renal cell carcinoma, small cell lung cancer, stage IV melanoma. The pharmaceutical composition of claim 20, wherein the inflammatory disorder, immune disorder, or autoimmune disorder is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, Atherosclerosis, inflammatory bowel disease, dryness, eczema, scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma and melanoma, ulcerative colitis, Atopic dermatitis, cystitis, spondylitis, uveitis, Behcets disease, rheumatic polymyalgia, giant cell arteritis, sarcoma-like disease, Kawasaki disease, juvenile idiopathic Arthritis, suppurative sweat gland inflammation, Sjögren's syndrome, dry arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's Disease, lupus, and lupus nephritis .