TW201211039A - Inhibitors of bruton's tyrosine kinase - Google Patents

Abstract

This application discloses 6-(2-Hydroxymethyl-phenyl)-2-methyl-2H-pyridazin-3-one derivatives according to generic Formula I: wherein, variables X, R, and Y4, are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatoty and auto immune diseases associated with aberrant B-cell proliferation, such as rheumatoid arthritis. Also disclosed are compositions containing compouads of Formula I and at least one carrier, diluent or excipient.

Description

201211039 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to the use of novel derivatives which inhibit Btk and are useful for the treatment of autoimmune diseases and inflammatory diseases caused by abnormal B cell activation. The novel 6-(2-hydroxymethyl-phenyl)_2-indenyl-2H-pyridazin-3-one derivatives described herein are useful for the treatment of arthritis. [Prior Art] Protein kinases constitute one of the largest family of human enzymes, and regulate many different signaling processes by adding phosphate groups to proteins (Ding Hunter, CW/1987 50:823-829). In particular, tyrosine kinase phosphorylates proteins over a portion of the tyrosine residues. The tyrosine kinase family includes members that control cell growth, migration, and differentiation. Abnormal kinase activity has been implicated in a variety of human diseases, including cancer, autoimmune diseases, and inflammatory diseases. Since protein kinases are key regulators of cell signaling, they provide targets for the regulation of cellular functions using small molecule kinase inhibitors and thus generate good drug design targets. In addition to therapeutic kinase-mediated disease processes, selective and potent inhibitors of kinase activity are also useful for studying cellular signaling processes and identifying therapeutically relevant cell counts. There is sufficient evidence that B cells play a key role in the pathogenesis of autoimmune diseases and/or inflammatory diseases. Protein-based therapeutics that deplete B cells, such as Rituxan, are effective against autoantibody-driven inflammatory diseases such as rheumatoid arthritis (Rastetter et al. (10) hv 2004 55:477). Thus, protein kinase inhibitors that play a role in B cell activation should be a suitable therapeutic agent for B cell mediated disease states, such as produced by autoantibody I57475.doc 201211039. Signaling via the B cell receptor (BCR) controls a range of B cell responses, including proliferation and differentiation into mature antibody producing cells. A key regulatory point for BCR* B cell activity, and abnormal signaling can lead to dysregulation of B cell proliferation and the formation of pathogenic autoantibodies that cause a variety of autoimmune diseases and/or inflammatory diseases. Bruton's tyrosine kinase (Btk) is a non-BCR-associated kinase that is proximal to the membrane and downstream of BCR. Btk deficiency has been shown to block BCR signaling, and thus inhibition of Btk may be An effective treatment to block b-cell mediated disease processes.

Btk is a member of the Tec family of tyrosine kinases and has been shown to be a key regulator of early b cell development and activation and survival of mature B cells (Khan et al., 1995 3:283; Ellmeier et al., /·5 Mei 2000) 192:1611). Mutations in Btk in humans cause X-linked agammaglobulinemia (XLA) (i Rosen^·, New Eng. J. Med. 1995 333:43 1 and Lindvall et al., / Mm(10)〇/_ 2005 203:200). These patients have immune dysfunction and show impaired B cell maturation, decreased immunoglobulin and peripheral B cell content, decreased τ cell-independent immune response, and decreased calcium movement after BCR stimulation. Evidence for the role of Btk in autoimmune diseases and inflammatory diseases has also been provided by the Btk-deficient mouse model. In preclinical murine models of systemic lupus erythematosus (SLE), Btk-deficient mice showed significant improvement in disease progression. In addition, Btk-deficient mice have resistance to collagen-induced arthritis (Jansson^. Holmdahl Clin. Exp. Immunol, 1993 94:459) ° 157475.doc 201211039 Selective Btk inhibitors have been demonstrated in mouse arthritis models Has a dose-dependent effect (Z. Pan et al, C/zem. Med CAem. 2007 2:58-61) 0

Btk is also expressed by cells other than B cells that may be involved in the disease process. For example, Btk is expressed by mast cells, and Btk-deficient bone marrow-derived mast cells exhibit impaired antigen-induced degranulation (Iwaki et al., */. valence/. C/zem. 2005 280:40261). This shows that Btk can be used to treat pathological mast cell responses such as allergies and asthma. In addition, monocytes from patients with XL A in which no Btk activity was present showed a decrease in TNFa production after stimulation (Horwood^A, J Exp Med 197: 1603, 2003). Due to jfc匕, TNFa-mediated inflammation can be modulated by small molecule Btk inhibitors. Furthermore, it has been reported that Btk plays a role in cell death (Islam and Smith / mmwno/. Rev. 2000 178:49), and therefore Btk inhibitors will be suitable for the treatment of certain B-segmental lymphomas and leukemias ( Feldh ah η et al., J. Med. 2005 201:1837). SUMMARY OF THE INVENTION The present application provides a Btk inhibitor compound of Formula I, a method of use thereof, as described below: This application provides a compound of Formula I,

Wherein: 157475.doc -6- 201211039 One is a single bond or a double bond; X is CH, CH2 or N; R is Η, -R1, _Rl_R2_R3, _R1_R3*_R2_R3; R1 is aryl, heteroaryl, bicyclohetero Or a cycloalkyl or heterocycloalkyl group, each optionally having one or more lower alkyl, hydroxy, hydroxy lower alkyl, lower alkoxy, halo, nitro, amine, decylamine Substituent, cyano, pendant oxy (0X0) or lower haloalkyl; R2 is -C(=〇), -c(=0)0, -C(=0)NR2, -NHC(=0 0, -C(R2')2, -0, _S, -C(=NH)NR2_ or -S(=0)2; each R2' is independently H or lower alkyl; R3 is H or R4; R4 is lower alkyl, lower haloalkyl, lower alkoxy, amine, lower alkylamino 'cycloalkylamino, lower dialkylamino, aryl, aryl Alkyl, alkylaryl, heteroaryl, alkylheteroaryl, heteroarylalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, heterocycloalkyl, alkylheterocycloalkane Or a heterocycloalkylalkyl group, a bicyclic cycloalkyl group, a bicycloheterocycloalkyl group, a spirocycloalkyl group, a spiroheterocycloalkyl group or a bicyclospirocycloalkyl group, each optionally having one or more lower alkanes base, , lower alkylalkylamino 'lower dialkylamino, hydroxy, hydroxy lower alkyl, lower alkoxy, lower alkyl alkenyl, fluorenyl, nitro, amine, amidino, Stuffed base, cyano group, pendant oxy group, fluorenyl group, low carbon ruthenium base, fluorenyl group, hydroxylamine group, carboxyl group, amine mercapto group, urethane group, halo lower alkoxy group, hetero a cycloalkyl or a halo lower alkyl group in which two low carbon building groups may together form j裒; Y4 is Y4a, Y4b, Y4e or Y4d; 157475.doc 201211039 Y4a is hydrazine or halogen; Y4b is a lower alkane a group, optionally substituted with one or more substituents selected from the group consisting of lower halohaloalkyl, halo, hydroxy, amine, cyano and lower alkoxy; Y4e is a lower alkylcycloalkyl, optionally Substituted by one or more substituents selected from the group consisting of lower alkyl, lower carbon, alkyl, halogen, hydroxy, amine, cyano and lower alkoxy; and Y is an amine group, optionally One or more low carbon alkyl groups, an alkoxy low carbon alkyl group or a hydroxy low carbon hospital base; or a pharmaceutically acceptable salt thereof. The present application provides a method of treating an inflammatory condition and/or an autoimmune condition comprising administering to a patient in need thereof a therapeutically effective amount of an inhibitor compound of the formula. The present application provides a pharmaceutical composition comprising a compound of any of the formulae in admixture with at least one pharmaceutically acceptable carrier, excipient or diluent. The phrase "a" or "system" as used herein refers to one or more of the entities, such as a compound, or one or more compounds, or at least one; therefore, the term "a" "," "one or more" and "at least one" may be used interchangeably herein. : "as defined above" means the broadest generality of each of the groups provided in the broadest range of information in this specification, as set forth below, and not explicitly defined in all other examples provided below. The substituents retain the broadest definition provided in the [Summary of the Invention] section 157475.doc 201211039. As used in this specification, the main "in the four-sex patent-to-inclusion" of the range of i i should be understood as having an open Meaning. Second, the terms should be understood as meaning "at least" with the phrase "at least inclusive t: when used in the context of a method, the term "comprising" means "including the steps, but may include others: : or in the case of a composition, the term "comprising" means =

The composition includes at least the features or components, but may also include other features or components. Unless otherwise specified, the meaning of "and/or" "including" is used.

Otherwise, the meaning of the word "as used in this article" is not exclusive to "any / or J or"

"M is independently used herein" to indicate that a variable is applied to any - in the case of the presence or absence of a variable having the same or different definitions in the same compound. Thus 'in R" appears twice and defined as "independently carbon or I", 'two R" can be carbon, two han|, both can be nitrogen, or one R" can be carbon and The other is nitrogen. Any occurrence of any number or formula in the drawing or description of the compound used or claimed in the present invention is defined at least once in each occurrence. Other definitions of occurrence. λ, as long as the combination of substituents and/or variables produces a stable compound, such combinations are permissible. The symbol at the end of the bond - 孰 孰 孰 键 键 ...... Each means a functional group or another chemical moiety and a 157475.doc 201211039 junction of the rest of the molecule. So, for example:

MeC(=0)0R4, where bu-0 or +<1 =>MeC(=0)0-<]. The bond drawn into the ring system (as opposed to the connection at a different apex) indicates that the bond can be attached to any suitable ring atom. The term "existing as appropriate" or "as appropriate" as used herein means that the subsequently described event or circumstance may (but is not required to) occur, and that this specification includes the occurrence of the event or circumstance and the event or circumstance has not occurred. situation. For example, "substituted as appropriate" means that a portion substituted as the case may have a hydrogen atom or a substituent. The phrase "key that exists as the case exists" means that the key may or may not exist, and the specification includes a single key, a double key, or a key. If the substituent is represented by "bond" or "absence", the atom attached to the substituent is directly bonded. The term "about J" is used herein to mean approximation, left and right, roughly or approximately. When the term "about" is used in conjunction with a numerical range, it can be modified by the boundary defined by the numerical values above and below. In general, the term "about J is used herein to modify a value that is 20% above and below the value. Certain compounds of formula I may exhibit tautomerism. Tautomeric compounds may be two or more The type of transformation exists. The proton transfer tautomer system is produced by the migration of a hydrogen atom covalently bonded between two atoms. The tautomer generally assumes an equilibrium state, and attempts to separate individual tautomers usually produce a mixture. The chemical and physical properties are consistent with the mixture of 157475.doc •10· 201211039. The equilibrium position depends on the chemical characteristics in the molecule. For example, 'in many aliphatic aldehydes and ketones (such as acetaldehyde) The ketone form predominates, while in the phenol, the enol form dominates. Common proton transfer tautomers include S iso/enol (-C(=0)-CH-SC(-0H)=CH-), Indoleamine/indenine (-C(=0)_NH-GC(-0H)=N-) and 脒(-C(=NR)-NH-SC(-NHR)=N-) tautomer The latter two are especially common in heteroaryl and heterocycles, and the invention encompasses all tautomeric forms of the compounds unless otherwise specified Otherwise, the technical terms used herein have the meanings commonly understood by those skilled in the art to which the present invention pertains. Various methods and materials known to those skilled in the art are mentioned herein. Standard reference works describing the general principles of pharmacology include Goodman and Gilman, 77ze Heart 仏〇 / , 1st edition, McGraw Hill c〇mpanies

Ine·, New York (2001). The invention may be carried out using any suitable materials and/or methods known to those skilled in the art. However, preferred materials and methods are described. Unless otherwise noted, the materials, reagents, and analogs mentioned in the following description and examples are available from commercial sources. The definitions described herein may be appended to form chemically relevant combinations such as "heteroalkylaryl", "dentate alkylheteroaryl", "arylalkylheterocyclyl", "alkylcarbonyl", "Alkoxyalkyl" and similar combinations thereof. When the term "alkyl" is used as a suffix after another term, as in "phenylalkyl" or "hydroxyalkyl", it is intended to mean that one or two alkyl groups as defined above are selected from another Substituted by a substituent of a particular named group. Thus, for example, "phenylalkylj" refers to an alkyl group having one to two phenyl substituents, and thus includes phenylhydrazine, phenethyl, and biphenyl. "Alkylaminoalkyl" has one to Two 157475.doc -11 - 201211039 alkyl groups of alkylamino substituents. "Hydroxyalkyl" includes 2-hydroxyethyl, hydrazine hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, methyl), 3_ by propyl and the like. Thus, the term "hydroxyalkyl" as used herein, is used to define a subgroup of heteroalkyl groups as defined hereinafter. The term _(aryl)alkyl means an unsubstituted alkyl or aralkyl group. The term (hetero)aryl refers to an aryl or heteroaryl group. The term "spirocycloalkyl" as used herein means a spirocyclic cycloalkyl group such as spiro[3.3] heptane. The term spiroheterocycloalkyl as used herein means spirocycloheteroalkyl, such as 2,6-diazaspiro[3.3]heptane.

The term "mercapto" as used herein denotes a radical of the formula _c(=〇)R, wherein R is hydrogen or lower alkyl as defined herein. The term "alkylcarbonyl" as used herein denotes a radical of the formula C(=〇)R, wherein R is alkyl as defined herein. The term Ck 醯 refers to a group containing 6 carbon atoms C(0)R. The term "arylcarbonyl" as used herein means a group of the formula c(=〇)R, wherein R is aryl; The term "benzhydryl" as used is wherein r is a aryl group of a phenyl group. The term "ester" as used herein denotes a group of the formula _c(=〇)〇R, wherein R is a lower alkyl group as defined herein. The term "alkyl" as used herein denotes a non-branched or branched chain, saturated, monovalent hydrocarbon residue containing from 1 to 1 carbon atoms. The term "lower alkyl" means a straight or branched hydrocarbon residue having 3 to 6 carbon atoms. As used herein, "Cki〇alkyl" means an alkyl group consisting of 1 to 10 carbons. Examples of alkyl groups include, but are not limited to, mercapto, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl 157475.doc 201211039 Base, hexyl lower alkyl, heptyl and octyl. When the term "alkyl" is used as a suffix after another term, such as in "phenylalkyl" or "alkyl", it is intended to mean that one or two alkyl groups as defined above are selected from another Substituted by a substituent of a particular named group. Thus, by way of example, S '"alkylene" means that the group R'R"_' is the opposite of phenyl and R" is an alkylene group as defined herein, provided that the point of attachment of the phenylalkyl moiety is On the alkylene group. Examples of arylalkyl groups include, but are not limited to, benzyl, phenethyl, 3-phenylpropyl. The term "arylalkyl" or "aralkyl" is similarly interpreted 'but R is an aryl group. The term "(hetero)arylalkyl" or "(hetero)arylxyl" is similarly explained, but R' is optionally aryl or heteroaryl. The term "haloalkyl" or "halo-lower alkyl" or "lower halo" refers to a radical containing from 1 to 6 carbon atoms in which one or more carbon atoms are replaced by one or more ii atoms. a linear or branched hydrocarbon residue. The term "alkylene" as used herein, unless otherwise indicated, denotes a divalent saturated straight chain hydrocarbon radical of one to ten carbon atoms (eg (CH2)n), or a branched chain of from 2 to 10 carbon atoms. A saturated divalent hydrocarbon group (for example, _cHMe- or -CH2CH(i-Pr)CH2_). Except for the condition of the fluorene group, the open valence of the alkyl group is not attached to the same atom. Examples of alkylene groups include, but are not limited to, anthracenylene, ethyl, propyl, 2-mercapto-propyl, 1,1-methyl-extended ethyl, butyl, 2-ethyl Base butyl. The term "alkoxy" as used herein means - 〇-alkyl, wherein fluorenyl is as defined above, such as decyloxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, Isobutoxy, tert-butoxy, pentyloxy, hexyloxy, including isomers thereof. As used herein, "lower alkoxy" means an alkoxy group having 157475.doc • 13· 201211039 having a "lower alkyl group" as defined previously. As used herein, "Cmo's alkoxy" means an alkyl group in which the alkyl group is Cl_1〇. The term "PCy3 J" refers to a phosphine that is trisubstituted with three cyclic moieties. The term "dentate alkoxy" or "fungyl-lower alkoxy" or "low carbon alkoxy" means one or more of them. a lower alkoxy group in which one carbon atom is substituted with one or more halogen atoms. The term "hydroxyalkyl" as used herein denotes an alkyl group, as defined herein, wherein one to three hydrogen atoms on different carbon atoms are replaced by a hydroxy group. The terms "alkylsulfonyl" and "arylsulfonyl" as used herein mean a radical of the formula -S(=0)2R where R is independently alkyl or aryl and alkyl and aryl are as As defined in this article. The term "heteroalkylsulfonyl" as used herein, refers to a radical of the formula -S(=〇)2R where R is a "heteroalkyl" group, as defined herein. The terms "alkylsulfonylamino" and "arylsulfonylamino" as used herein mean a radical of the formula -NR'S(=〇)2R, wherein r is alkyl or aryl 'R is hydrogen or C!·3 alkyl group' and the alkyl group and the aryl group are as defined herein. The term "cycloalkyl" as used herein means a saturated carbocyclic ring containing from 3 to 8 carbon atoms, i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. As used herein, "CM cycloalkyl" or "lower alkyl" refers to a cycloalkyl group consisting of 3 to 7 carbons in the carbocyclic ring. As used herein, the term "slow-base" refers to a moiety of a group in which one of the hydrogen atoms has been recalcinated, provided that the point of attachment of the miscellaneous group is via a carbon atom. The term "carboxy" refers to the -C〇2H moiety. The term "heteroaryl" or "heteroaromatic" as used herein, means having 5 I57475.doc 14-201211039 fluorene atoms and having at least one aromatic or partially unsaturated ring (containing four to eight atoms per ring). A monocyclic or bicyclic group having one or more N, 0 or S heteroatoms, the remaining ring atoms being carbon, provided that the point of attachment of the heteroaryl group is on the aromatic or partially unsaturated ring. As is well known to those skilled in the art, 'heteroaryl rings have less aromaticity than their all carbon counterparts. Thus, for the purposes of the present invention, the heteroaryl group only has to have some degree of aromatic I1 heteroaryl group which may be optionally substituted as defined below. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and fluorene to 3 heteroatoms including, but not limited to, pyridyl, pyrimidinyl, pyrazinyl, oxazinyl, pyrrole base,. Bizozolyl, imidazolyl, oxazolyl, 4,5-dihydro-oxazolyl, 5,6-dihydro-4-indole-[ι,3]oxazolyl, isoxazole, thiazole, isothiazole, two An oxazoline, an oxadiazole or an oxadiazoline, optionally substituted by one or more, preferably one or two substituents selected from the group consisting of a hydroxyl group, a cyano group, an alkyl group, an alkoxy group, a thio group, Lower alkoxy, alkylthio, functional, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, dentate, amine, alkylamino, dialkylamino, Aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl, decyl, alkoxycarbonyl and aminemethanyl, alkylamine fluorenyl, dialkylamine decyl, aryl Aminomethyl thiol, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazole, benzisoxazole, benzopyrene, 嗉, 嗉Pyridyl, 5,6,7,8-tetrahydro-[1,6]acridinyl and benzisothiophene. The bicyclic moiety may be substituted on either ring, however, the attachment point is on a ring containing a hetero atom. The term "aryl" means a monovalent aromatic carbon containing from 6 to 1 carbon ring atoms. 157475.doc • 15· 201211039 Ring monocyclic or bicyclic system. Examples of the aryl moiety include a phenyl group and a decyl group. The term "heterocyclyl", "heterocycloalkyl" or "heterocycle" as used herein denotes a group of - or more rings, preferably one to two rings (including a spiro ring system), and each ring has three to A monovalent saturated ring group of eight atoms having one or more ring heteroatoms (selected from N, 〇 or S(〇) G.2) and, unless otherwise indicated, may optionally pass one or more And preferably one or two substituents selected from the group consisting of a hydroxyl group, a pendant oxy group, a cyano group, a lower alkyl group, a lower alkoxy group, a lower alkoxy group, an alkylthio group, a halogen group , lower carbon-alkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amine, alkylamino, alkylsulfonyl, Iarylsulfonyl, alkylaminosulfonyl, aryl Aminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino and ionic forms thereof. Examples of heterocyclic groups include, but are not limited to, sputum-based, beta-pyridazinyl, pyridyl, azetidinyl, pyrrolidinyl, hexahydroazetyl, oxetane, Tetrahydrofuran. Nanji, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydrogen. Nanji, thio-indenyl, p-quinacridyl and imidazolyl, and their ionic forms. An example may also be a bicyclic ring such as 3,8-diaza-bicyclo[3 2 1;]octane' 2,5-diaza-bicyclo[22.2]octane or octahydro-0-azine and [2 , 14] [1, 4] evil smell. The present application discloses 6-(2-hydroxyindolyl-phenyl)-2-indolyl-2H-pyridazine-3-one derivatives according to formula I, wherein the variables are as defined herein: 157475. Doc •16· 201211039 ο

sheet. The term "as defined herein" means the broadest definition of each group as provided in the [Summary of the Invention] section of the specification, the [embodiment] of the specification, or the broadest scope of the invention. In all other aspects, variations and examples provided, the substituents which may be present in the examples and which are not explicitly defined retain the [invention] portion of the specification, the [embodiment] of the present specification or the broadest The broadest definition provided in the scope of the patent application. The compound of formula I inhibits Bruton's tyrosine kinase (Btk). Activation by the supernatant kinase activates the phospholipase, which in turn stimulates the release of the proinflammatory mediator. The compound of Formula 1 having a 4-ring system side chain exhibits an unexpected increase in inhibitory activity as compared to an analog having other side chains. Significantly, the fluorine substitution on the unsaturated side chain has unexpectedly increased the effect in human whole blood by about 5_i 0 times. In addition, the fluorinated side chains provide an increased 'simultaneous' combination with the molecular pyridazinone core, which generally has an unexpectedly improved safety profile compared to molecules having a ketone core. In particular, the pyridazinone core molecule does not undergo an unacceptable degree of covalent binding due to reactive metabolites during metabolism. Formula I compounds are indicated for the treatment of arthritis and other inflammatory diseases and autoimmunity 157475.doc • 17· 201211039 Disease. Because it is 4 曰M, the compound according to formula I is suitable for the treatment of arthritis. The sputum is suitable for inhibiting Btk in cells and is suitable for regulating sputum cell development. The present month additionally comprises a pharmaceutical composition comprising a compound of formula I in admixture with a pharmaceutically acceptable carrier, excipient or diluent. This claim provides a compound of formula I,

Wherein: - is a bond or a double bond; X is CH, CH2 or N; R is Η, -R1, r1_r34 _r2_r3; R1 is aryl, heteroaryl, bicycloheteroaryl, cycloalkyl or heterocycloalkane a group, each optionally having one or more lower alkyl, hydroxy, hydroxy lower alkyl, lower alkoxy, halo, nitro, amine, amidino, cyano, pendant or Substituted by a low carbon halogen group; R2 is -C(=0), -C(=0)0, -C(=0)NR2., _NHC(=0)0, -C(R2')2, -O , -S, -C(=NH)NR2 or -S( = 〇)2; each R2' is independently H or a low carbon yard; R3 is H or R4; R4 is a lower alkyl, lower alkane Alkyl, lower alkoxy, amino, low carbon 157475.doc -18- 201211039 alkylamino, cycloalkylamino, lower dialkylamino, aryl, arylalkyl, alkyl , heteroaryl, alkylheteroaryl, heteroarylalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, heterocycloalkyl, alkylheterocycloalkyl, heterocycloalkyl An alkyl group, a bicyclic cycloalkyl group, a bicyclic heterocycloalkyl group, a spirocycloalkyl group, a spiroheteroalkyl group or a bicyclospirocycloalkyl group, each optionally having one or more lower alkyl groups, a functional group, Carboalkylamino, lower dialkylamino, hydroxy, hydroxy lower alkyl, lower alkoxy, lower alkyl hydrazino, yl, nitro, amine, decyl, fluorenyl, a cyano group, a pendant oxy group, a sulfonyl group, a low carbon alkyl group, a sulfhydryl group, a transaminyl group, a buffer group, an amine carbenyl group, a urethane group, a functional group lower alkoxy group, a heterocycloalkyl or a halo lower alkyl group in which two lower carbon groups may form a ring together; Y4 is Y4a, Y4b, y4c4 Y4d; ¥43 is 1^ or halogen; Y4b is lower alkyl, The case is substituted by one or more substituents selected from the group consisting of a lower halohaloalkyl group, an iS element, a hydroxyl group, an amine group, a cyano group and a lower carbon alkoxy group; Y4e is a lower alkylcycloalkyl group, as the case may be Or a plurality of substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amine, cyano and lower alkoxy; and Y4d is an amine group, optionally a plurality of lower alkyl, alkoxy lower alkyl or hydroxy lower alkyl; or a pharmaceutically acceptable salt thereof. In addition, it is to be understood that each of the embodiments disclosed herein with respect to particular residues R, x, and Y4 can be associated with any of the residues R, 157 157475.doc -19- 201211039 and γ4 as disclosed herein. Other embodiments are combined. The application provides a compound of formula I, wherein two: is a double bond; and X is N. This application provides a compound of formula I wherein = is a single bond; and X is CH2. This application provides a compound of formula I wherein two are double bonds; and X is CH. This application provides a compound of formula I, wherein two are double bonds; 乂 is ^^; and the ruler is -r^-r3 〇 This application provides a compound of the formula wherein > is a double bond; χ is N; Is -Rl-R3; and R is a pyridyl group. The present invention provides a compound of formula I, wherein: U: is a double bond; χ &Ν; and a ruler. The present invention provides a compound of formula I, wherein: ^ is a double bond; χ is N; R is -Ri-R^R3; and the ruthenium is pyridyl β. The present invention provides a compound of the formula wherein > is a double bond; χ is N; R is W-R3; is a pyridyl D group; and the ruler 3 is a ruler 4. The present invention provides a compound of formula J, wherein > is a double bond; X is N; R is -R _r2-R3; R 丨 is. Pyridyl; and R3 is R4. The present application provides a compound of the formula wherein > is a double bond; X is n; r is -W-R3; ratio. Base; R^R4; and 丫 is y4b. 1 Shen's case provides a compound of formula I, wherein > is a double bond; χ is N; R is -RLr2-r3; R1 is pyridyl; R3 is R4; and 丫 is Y4b. The present invention provides a compound of formula I, wherein > is a double bond; X is N; r is _Rl-R2-R3; RH is fixed; R2 is -C(=〇), c(r2,)2 , _〇_, _S_, -S(=0)2; R3 is R4; and Y is Y4b. 157475.doc -20- 201211039 This application provides a compound of formula I, wherein = is a double bond; χ is N; r is -R1-R2_r3; 1^ is a ° ratio; R2 is -C(=0); R3 Is r4; and γ is Y4b. This application provides compounds of formula I wherein two are double bonds; xgN; R is -R^-R3; Hi is pyridyl; R3 is R4; and Y4b is a third butyl group. This application provides a compound of formula I wherein = is a double bond; X is N; R is _111-foot 2 士3; R1 is pyridyl; R3 is R4; and Y4b is a third butyl group.

This application provides a compound of formula I wherein = is a double bond; X is N; R is · r1-r2-r3; R1 is a ratio of bite; R3 is R4; and R2 is -S(=0)2, wherein R4 is a lower alkyl group. This application provides a compound of formula I, wherein two are double bonds; X is N; R is RLr2-R3; 丨 is rididyl; R2 is -C(CH3)2; R3 is R4; and R4 is optionally Lower alkylamino, lower dialkylamino or heterocycloalkyl substituted by one or more lower alkyl groups. The application provides a compound of formula I, wherein = is a double bond; X is N; R is W-RlR3; R1 is phenyl or alpha to a bite; R%_C(= 〇); "is !^; and R4 is Morpholine or piperazine, optionally substituted with one or more lower alkyl groups. The present application provides a compound of formula I wherein = is a double bond; X is N; and Y4 is a third butyl group. a compound I wherein two are single bonds; X is CH2;

Wherein Y5 and Y6 are independently hydrazine, lower alkyl or lower haloxyalkyl. 157475.doc •21- · 201211039 This application provides a compound of formula I, wherein two are double bonds; hydrazine is CH;

Y4 is wherein Y5 and Y6 are independently hydrazine, lower alkyl or lower haloxyalkyl. The present invention provides a compound of formula I, one of which is a double bond; X is hydrazine; and Υ4 is

八中Υ is Η, _, low alkyl or low carbon _ alkyl. The present application provides a compound of formula I, wherein two are double bonds; X is hydrazine; and Υ4 is wherein Υ5 and Υ6 are independently hydrazine or lower alkyl. The present application provides a compound of formula I, wherein = is a double bond; X is hydrazine; Υ4 is a third butyl group; 尺 is _Ri_R3; Ri is pyridyl or pyrazolopyrazine; R3 is R4; and R4 is optionally Substituted lower alkyl, heterocycloalkyl or alkylheterocycloalkyl. This application provides a compound of formula I, wherein = is a double bond; X is hydrazine; Y4 is a third butyl group; R is -RLrIr3; R is D for a pyridyl group; R2 is -C(CH3)2; R3 is R4 And R4 is a lower alkylamino group, a lower dialkylamino group or a heterocycloalkyl group optionally substituted with one or more lower alkyl groups. This application provides a compound of formula I wherein two are double bonds; X is hydrazine; Y4 157475.doc -22. 201211039 is 3 tert-butyl; R is _R丨_R2_R3; R1 is pyridyl; r2 is; R3 R4; and R4 is optionally substituted heterocycloalkyl or bicyclospirocycled. The present application provides a compound of formula I, wherein two are double bonds; 乂 is 1^; Y4 is 3 tert-butyl; R is _RLR2_r3; R is pyridyl; Han 2 is {di); R3 is R4; And R4 is an optionally substituted morpholine or piperazine. The present application provides a compound of the formula 选自 selected from the group consisting of: a third butyl group 2_(3_{5_[5_(1-ethylamino)methylmethyl). Di-methyl-6_sideoxy·1>6-dihydro-pyridazine_3_yl}_2-hydroxymethyl-carbyl)-8-fluoro-2open-pyrazine-1-one;6-tert-butyl_8_fluoro_2_(2.hydroxyindole_3^-mercapto-5-[5_(morpholine-4-carbonyl)-pyridin-2-ylamino);|_6_ side oxygen Base_丨,6_二氲_哒azine_3_基卜phenyl)_ 2//-pyridazine+one; 6-t-butyl-8-fluoro-2-{2-hydroxyindolyl-3 -[5-(5-methanesulfonyl-pyridinyl-2-ylamino)-1-methyl_6_sideoxy-丨,6-dihydro-pyridazine_3_yl]-benzene Keb 2 open-pyridazine ketone; 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(3-methoxy-azetidine) -1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-sideoxy-i,6-diaza-anthracene_3_yl}-phenyl)_2pyridazine _ ketone; 6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3-{l-fluorenyl_5-[5-(8-fluorenyl) 3,8-diaza -bicyclo[3.2.1]oct-3-ylmethyl)-pyridin-2-ylamino]-6-o-oxy-1,6-dihydro-pyridazin-3-yl)-phenylpyridazine -1-ketone; 6_t-butyl-2_-(3-{5-[5 -(2-dimethylamino-indenyl-dimethyl-ethoxybidin-2-ylamino)-1-indolyl-6-oxirane-1,6-dihydro-pyridazine- 3-157475.doc •23· 201211039 yl}-2-hydroxymethyl-phenyl)-8-fluoro-2/7-phthalazin-1-one; 2-{3-[5-(5-aza Cyclobutane-1-ylmethyl-pyridin-2-ylamino)-1-indolyl-6-flavonyl-1,6-diaza-enriched-3-yl]-2-purinyl -bens} - 6 -Secondyl-8 - said -2//· σ too 嘻-1 -嗣; 6-t-butyl 2-(3-[5-(5-didecylamine)曱 曱 比 -2- -2- 基 基 基 基 基 -1 -1 -1 - - - -1 -1 -1 -1 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦 秦8 -say - 2Η -Blowing -1 _嗣, 6-t-butyl-2_(3-{5-[(111,58)-5-(3,8-diaza-bicyclo[3.2.1] Octyl-8-yl)-.t-but-2-ylamino]-1 -mercapto-6-o-oxy-1,6-di-rho-indole-3-yl}-2-hydroxyl Mercapto-phenyl)-8-fluoro-2-indole-pyridazin-1-one; 6-{6-[3-(6-secondbutyl-8-a-1-sideoxy-1Η-. too ° Qin-2 -yl)-2 - thiol-styl]-2-mercapto-3 - oxo 2,3 -diaza- olfactory-4 -ylamino}-Ν, Ν- Dimethyl-nicotine decylamine; 6-second butyl-8-gas-2-{2- thiol-3-(1-mercapto-6-side -5- (5-throat than said Yue-yl 2 - yl amino) -1,6-N - Qin ° even ° -3---yl] - phenyl} -2Η_. Taichung-1 -ketone; 6-t-butyl-8-gas (-2-(3-{5-[5-(2-]-yl-1,1-didecyl-ethoxy)- ° ratio. -2 -aminoamino]-1 -mercapto-6-sideoxy-1,6-diaza-enhanced-3_yl} - 2 - fluorenyl-phenyl)-2 // -σ太嗓-1 -copper, 2-(3-{5-[5-(2-azetidin-1-yl-1,1-didecylethoxy)-pyrobitone-2 -aminoamino]-1-indolyl-6-o-oxy-1,6-di-rho-s-diazol-3-yl}-2-indolyl-phenyl)-6-t-butyl- 8 - said -2 -. too. Qin-1 - oxime, 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(2-hydroxy-2-) Mercapto-propoxy)-D ratio. Benz-2-ylamino]-1-indolyl-6-oxirane-1,6-diaza daindole-3_ 157475.doc -24- 201211039 base} -phenyl)-2β-pyridazin-1-one; 2-[8-fluoro-2-(2-hydroxymethyl_3_{1-methyl-5-[5-(morpholin-4-carbonyl)) -pyridin-2-ylamino]-6-yloxy-oxime, 6-dihydro-pyridazine-3-yl}-phenyl)-1-yloxy-1,2-dihydro-isoquine Phenyl-6-yl]-2-methyl-propionitrile; 6-t-butyl-8-fluoro-2-(3-{5-[5-((S)-2-hydroxy-3-pyreneoxy) -propenyl)-"bipyridin-2-ylamino]-1-methyl-6-o-oxy-1,6-dihydro-pyridazinyl}-2-hydroxyindolyl-phenyl )-2// -pyridazine-1-_ ; 6_t-butyl_8_fluoro-2-(3_{5-[5-((R)-2-hydroxy-3.methoxy-propoxy)-° Bis-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazinyl}-2-hydroxymethyl-phenyl)-277-pyridazine-1- Ketone; 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-U-indolyl-5-[5-((S)-U曱ylpyrrolidin-2-yl) -°-pyridin-2-ylamino]-6-sideoxy-1,6-dihydro-pyridazin-3-yl}-phenylpyridazin-1-one; 6-t-butyl-8- Fluor-2-(2-hydroxymethyl-3-{l-methyl-5-[5-((R)-kmethylpyrrolidin-2-yl)-)pyridin-2-ylamino -6-Sideoxy-1,6-dihydro-pyridazine-3-yl}-phenyl)-2//-pyridazin-1-one; ό-{6-[3-(6- Tributyl-8-fluoro-1-oxooxy-1"-pyridazin-2-yl)-2-hydroxydecyl-phenyl]-2-mercapto-3-yloxy-2,3 - Dihydro- _ ° -4 -4 -4 -4 -4 -4 -4 -4 -4 ; ; ; ; ; ; 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 -(4-hydroxy-4-methyl "piperidin-1-carbonyl"-pyridin-2-ylaminol l·1·methyl-6-oxooxy-1,6-dihydro-pyridazine-3 -yl}-phenyl)-2//-pyridazine-butanone; 6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3-{i-methyl-5_[5-(6- Mercapto-2,6-diaza-spiro[3.3]heptan-2-yl)_ Pyridylamino]-6-sideoxy 157475.doc • 25- 201211039 Dihydro-pyridazin-3-yl}-phenyl)-2/ί-pyridazin-1-one; 6-t-butyl -2-{3-[5-(5-ethanesulfonylpyridin-2-ylamino)-1_indolyl-6-yloxy-1,6-dihydro-pyridazine-3- 2-hydroxymethyl-phenyl}-8-fluoro-2 ugly-pyridazin-1-one; 6-t-butyl-8-fluoro-2-(2-hydroxyindole-3-{ 1-methyl-6-oxo-5-[5-(propane-2-sulfonyl)-pyridin-2-ylamino]-1,6-dihydro-purine _3-yl}- Phenyl)-2dan-pyridazin-1-one; 6-t-butyl-8-fluoro-2-(3-{5-[5-(2-hydroxy-ethylthio))-pyridinium -2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxyindolyl-phenyl)-2//-pyridazine 1-ketone; 6-t-butyl-8-say-2-(3-{5-[5-(2-amino-ethyl)-D-bit-2-ylamino]-1 -mercapto-6-o-oxy-1,6-dihydro-pyridazin-3-yl}-2-hydroxyindolyl-styl)-2open-pyridazin-1-one; 6-third -8-fluoro-2-(2-]-indolyl-3-{5-[5-(4-isopropyl-2-carbo-1)-pyridin-2-ylamino]-1-yl -6-o-oxy-1,6-dihydro-pyridazin-3-yl}-styl)-2//-pyridazin-1-one; 6-t-butyl-8-fluoro-2 -(2-hydroxyindolyl-3-{imethyl-5-[5 -(l-decyl-pyrrolidin-3-yl)-. Bis-2-ylamino]_6_sideoxy_i,6-dihydro-pyridazine_3_yl}-phenyl)-2//-Blowing -1-_; 6_Secondyl -8 -Gas-2 - {2 - via methyl-3 - [ 5 - (1,-isopropyl-7,2',3',4',5',6'-hexahydro-[3, 4']-bipyridyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}_2孖-pyridazinone ; 6-t-butyl-2-{3-[5-(Γ-ethyl hydrazine. ratio. -6-ylamino)-1-methyl-6- oxirane-1,6-di Hydrogen-嚷°秦-3-yl]-157475.doc • 26 - 201211039 2-Hydroxymethyl-phenyl}-8-fluoro-2//-pyridazin-1-one; 6-t-butyl- 2-{3-[5-(l,5-Dimethyl-1//-pyrazol-3-ylamino)-1-indolyl-6-yloxy-1,6-diaza-da嗓-3 -yl]-2 - fluorenyl-phenyl}-8-fluoro-2-open-boiling 嗓--; 6-t-butyl-8-fluoro-2-(2-hydroxyl) Base-3-{l-mercapto-5-[5-((S)-l-fluorenyl-σ ratio p. determinate-3-yl)-° ratio σ定-2 _ylamino]-6 - sideoxy·1,6-diaza-enanti-3-indenyl}-phenyl)-2 //-σ太嘻-1 ·嗣, 6-t-butyl-8-fluoro-2·( 2-hydroxymethyl-3-{1-methyl-5-[5-((R)-l-fluorenyl-σpyrolozolidine-3-yl)-° ratio -22 -ylamino group ]-6 - side oxygen Base-1,6 ·diaza-seudoquinone-3-yl}-phenyl)-2//-pyridazin-1-one; 6-t-butyl-8-fluoro-2-{2-hydroxyl Base-3-[1-indolyl-5·(4-mercapto-3,4,5,6-tetra-rat-2//_[1,2,]-in combination with 嗓-5|-ylamino group )-6-Sideoxy-1,6-two-rat-°°°Qin-3-yl]-phenyl}-2 吹σ秦-1 -嗣; 6-Secondyl-2-{3- [5-(5-Cyclobutylaminomethyl-°°°Qin-2-ylamino)-1-indolyl-6-yloxy-1,6-diaza-dar-3-yl ]-2-fluorenyl-phenyl} - 8 · gas-2 /f -σ太嘻-1 -嗣, 6-t-butyl-2-(3-{5-[5-(2-two Methylamino-ethoxybisazine-2-ylamino]-1-methyl-6-o-oxy-1,6-dihydro-pyridazin-3-yl}-2-hydroxyindenyl- Phenyl)·8-gas-2 7/-ϋ太嘻-1 -嗣, 6-second butyl-8-gas-2-(2-methyl-3-{1-methyl-5- [5-(4-Methyl·Phenyl-l-ylmethyl)-° ratio σ-Qin-2-ylamino]-6-sideoxy-1,6-dihydroindan-3-yl} -phenyl)-2dan-pyridazin-1-one; 6-t-butyl-2-(3-{5-[5·(2·didecylamino-1,1-dimethyl-) Ethoxy)-σ-pyridin-2-ylamino]-1-indolyl-6-sideoxy-1,6-diaza-da--3-157475.doc •27- 201211039 】}-2 -hydroxyl-based-stupid)_8- Fluorine-2-pyridazin-1-one; 6_t-butyl-2-(3-{5-[6-(2-dimethylamino)-1,1-dimethyl-ethoxy )-pyridazin-3-ylamino]_1_methyl_6_sideoxy '6-dihydro-pyridazin-3-yl}-2-methyl-phenyl)_8_fluoro-2 ugly - oxazin-1-one; 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(l-methyl-piperidine- 4-yl)-pyridazin-3-ylamino]-6-oxo-i,6-dihydro-pyridazin-3-yl}-phenyl)-2//-pyridazin-1-one ; 6_Ter Butyl-8-fluoro-2-(2-hydroxymethyl-3-{l-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)- . Bipyridin-2-ylamino]-6-sideoxy-1,6-dihydro-pyridazin-3-yl}-phenyl)-2//-pyrazine-1-broth | ; 6- Tributyl-8-fluoro-2-[2-hydroxymethyl-3-(5-{5-[(2-decyloxy-ethylamino)-methyl]pyridin-2-ylamino) }-1_Methyl_6_sideoxy-l,6-dihydro-哒°qin-3-yl)-phenyl]-2//- blowing "Qin-1-one; 6-Third -8-fluoro-2_(2-hydroxyindolyl-3-{l-fluorenyl-5-[5-((lS,4S)-5-methyl-2,5-diaza-bicyclo[2.2 .1]heptyl-2-ylhydrazinobi-2-ylamino]-6-oxooxy-1,6-dihydro-pyridazine_3· phenylphenylpyrazine 丨 ketone; 6 _Secondyl hydrazine_2_{2_hydroxymethyl_3_[5_(5_{[(2曱 oxy-ethyl)-indolyl-amino]-indenyl}-pyridyl-2-ylamino )]_曱 __6_ pendant oxy-1,6-dihydro-pyridazin-3-yl]-stylpyrazin-1-one; 6-t-butyl Ifluoro-2-(2_ Methyl _3_{1_ fluorenyl, 5_[6(4^-yl- oxazin-1-yl)-pyridazin-3-ylamino]]6_sideoxy_i,6-dihydro-pyridazinebenzene ))-2--pyridazine-1-isj ; ',3·yl Ι [6_((1S,4S)-ylamino]-6 ό-t-butyl-8-1-2-(2- Hydroxymethyl-3-{1-methyl-5-methyl-2,5-diaza-bicyclo[2 21;|hepta-2-yl)-pyridazine 157475.doc -28- 201211039 -1 6 - 一气-°达°秦-3-基}_本基)-2 //-β太唤-1 -付; 2-(3-{5-[5-(azetidin-1- Carbonyl)-acridine-2.ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazine_3·kib 2-hydroxymethyl·phenyl)-6- Third butyl-8-fluoro-2//- blowing °H-1·one; 6-t-butyl-2-(3-{5-[5-(1,1-di-oxy-U6) - thiomorpholine-4-carbonyl)-pyridin-2-ylamino]_ι·methyl-oxyl-oxime, 6-dihydro-pyridazin-3-yl}-2-hydroxydecyl-phenyl )_8_Fluoro-2dan-pyridazinone; 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{l-fluorenyl-5-[5-(2-oxa) -6-aza-spiro[3.3]heptane-6-carbonyl)-pyridin-2-ylamino]-6-o-oxy-1,6-dihydro-pyridazin-3-yl}-phenyl _2 ugly-pyridazin-1-one; 6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3-{l-methyl-5-[5-(6-methyl-) 2,6-diaza-spiro[3.3]heptan-2-carbonyl)-pyridinylamino]-6-o-oxy-1,6-dihydro- oleoxazin-3-ylphenylphenyl Ketone; 6-{6-[3-(6-t-butyl_8_fluoro-丨_sideoxy_17^pyridazine-2-yl)_2-hydroxymethyl-phenyl]-2-indole Base_3_sideoxy-2,3-dihydro-pyridazine-4-ylamino (2-didecylamino-ethyl)-nicotinium amide; 6-{6-[3-( 6-second _8_Fluoro-丨_sideoxy-pyridazine_2·yl)_2_hydroxyindole-phenyl]-2-indenyl_3_sideoxy-2,3_dihydro-indole嗪_4_基胺基卜#_(2-hydroxy-ethyl)-indole_methyl-nicotinamide; 1-(6-{6-[3-(6_t-butyl-8-) Fluorine·丨_sideoxy_1 oxazin-2-yl)_2· fluorenyl-phenyl]-2-mercapto_3_sideoxy-2,3_two-coating_Qing _4_ base Aminopyridin-3-carbonyl)-azetidine_3_indenenitrile; 6-first butyl-8-1-2-(2- via f-yl-3-{5_[5_(3- By Kibillo.定-1-叛基)-吼 Bit-2-ylamino-indenyl-tert-oxyl^6-dihydro-chimazine_3_ 157475.doc 29· 201211039 base}-phenyl)-2//-呔Pyrazin-1-one; 6-t-butyl-8-say-2-(2-fluoroindolyl-3-{5-[5-(4-light base-slightly-fixed-1-carboyl) -°Bitter-2-ylamino]-1-indolyl-6-tertiaryoxy-1,6-diaza-adadridin-3-yl}-phenyl)-2//-pyridazine-1 -ketone; 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-f-yl-piperidin-1 -yl)- ° ratio σ定-2 -ylamino]-6-sideoxy-1,6-diaza-enhanced °-3-3-yl} _phenyl)-2 吹σ秦-1 - @同,6· Tert-butyl-2-(3-{5-[5-(〇1,2-dihydroxy-ethyl)-.pyrazin-2-ylamino]-1-indolyl-6-sideoxy -1,6-di-r-indole-3-yl}-2-methyl-phenyl)-8-fail-2. Too-1 -嗣, 2-{3-[5-(5-azetidin-1-ylindenyl-1-methyl-1/^pyrazol-3-ylamino)-1- Indole-6-sideoxy-1,6-di-rho-champry-chrylen-3-yl]-2-methyl-phenyl}-6-tert-butyl-8-fluoro-2//- Pyridazin-1-one; 6-t-butyl-8-fluoro-2-{2-hydroxyindolyl-3-[1-indolyl-5-(5-methyl-4,5,6,7 -tetrahydro-pyrazolo[1,5·α]pyrazin-2-ylamino)-6-o-oxy-1,6-diaza-dana-3-ylbuphenyl} - 2 / /-Blowing Qin-1 - @同,6-Tertibutyl-8-fluoro-2-{2-hydroxyindolyl-3-[1-indolyl-5-(5-oxebutane- 3-yl- 4,5,6,7-tetrazole-° ratio 0 弁[l,5-a]°tb嗓-2-ylamino)-6-sideoxy-1,6-diaza - ° 嗓 -3 -yl]-phenyl} - 2 blowing ° Qin-1 - 3 with, 6-t-butyl-8-fluoro. ratio. D--6-ylamino)-1 -mercapto-6-o-oxy-1,6-diaza-oxa-3-yl]-2-hydroxyindolyl-phenylpyridazin-1-one; 6-t-butyl-8-fluoro-2-{2-hydroxyindolyl-3-[5-(1*-nonanesulfonyl-1',2',3',4',5', 6^hexahydro-[3,4']bipyridin-6-ylamino)-1-indolyl-6-sideoxy 157475.doc -30· 201211039 yl-1,6-diaza-jianxi-3 -yl]-phenyl} - 2 7/-Blowing 嘻-1 -嗣; 2-{3-[5-(Γ-醯醯-Γ, 2, 3, 4丨, 5f56, · hexahydro- [3,4l]bipyridin-6-ylamino)-l-fluorenyl-6-flavoryl-l,6-diaza-glucosin-3-yl]-2-pyridyl-phenyl }-6-dibutyl-8-gas-2-blowing σ-Q-1 -S with; 6-second butyl-8-rat-2-{2_light methyl-3-[5-( 4-Lightyl-4-mercapto-3,4,5,6-tetrahydro-2//-[1,3']bipyridyl-6'-ylamino)-1-methyl-6-side Oxy-1,6-di-mouse-gate-3-yl]-phenyl}-σ too σ-Qin-1 - oxime, 6-t-butyl-8-fluoro-2-{2-hydroxymethyl -3-[5-(4-hydroxy-3,4,5,6-tetrahydro-2//-(1,31)bipyridin-6'-ylamino)-1-indolyl-6-side Oxy-1,6-dihydro- 嗓-3-yl]-phenyl}-2//~Blowing 酉-1 - 酉; 6-T-butyl-8-fluoro-2-(2- Hydroxymercapto-3-{1-mercapto-5-[5-(( lR,5S)-3-indolyl-3,8-diaza-bicyclo[3·2·1]oct-8-yl)-acridin-2-ylamino]-6-sideoxy-1 ,6-diaza-d.qin-3-yl}-phenyl)-2 blowing σ Qin-1 -嗣, 6-t-butyl-8-fluoro-2-{2-hydroxyindolyl-3- [1-Methyl·5-(indolyl-1,2',3',4',5',6'.hexahydro-[3,4]. Bipyridin-6-ylamino 6-o-oxy-1,6-dihydro-pyridazin-3-yl]-phenylpyridazin-1-one; 6-t-butyl-2-(3-{5-[1- ((R)-2,3-dihydroxy-propyl)-1//-pyrazol-3-ylamino]-1-indolyl-6-yloxy-1,6-dihydro-pyridazine -3-yl}-2-hydroxymethyl-phenyl)-8•gas-blowing °Q-1 -嗣, 6-second butyl-2-(3-{5-[5-(4-B --嗓嗓-1-yl)-° ratio. 2-amino-yl-1-methyl-6-tertiaryoxy-1,6-diaza-s--3-yl}-2- By methyl-phenyl)· 8-rat-2//Blowing 嘻-1 -嗣, 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[ 1- (2-hydroxy·2·decyl-propyl)-1 //° ratio. -3 - ylamino]-1-mercapto-6 - flavonyl-1,6-diaza-d ° Qin-3 _ 157475.doc -31- 201211039 }}-phenyl)-2// - ° too. Qin-β. 2-(8-H ·2-{2-hydroxyindoleyl][曱曱基_5 (广曱基-1', 2', 3', 4', 5,, 6'-hexahydro- [3,4,]bipyridyl-6-ylamino)_6_sideoxy-1,6-dihydro-pyridazin-3-yl]-stupyloxy-oxime, 2_dihydro-isoquinoline Phenyl-6(6))-2-methyl-propionitrile; 2-(2-{3-[5-(5-cyclohepta-p-butylmethyljmethyl-1/7-pyrazole_3_yl) Amino)-1-indolyl-6-dioxyl-indole, 6-dihydropyridazine_3_yl]_2hydroxymethyl-phenyl phenyloxy-dihydro-isoquinoline_6_ ) _2 曱 丙 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- -1-methyl-oxyl-oxime, 6-dihydropyridazine-3-yl}-2-hydroxyindole-phenyl)-8-fluoro-oxyl-oxime, 2-dihydro-isoquinoline-6 Base]_2曱基-丙猜, 2-(8-fluoro-2-{2-hydroxyindolyl _5_(5-methyl_4 5 6 7 tetrahydro-pyrazolo[1,5-α Pyrazin-2-ylamino side oxy-oxime, 6-dihydro-oxazinyl]-phenyl}-1-sidedoxy-1,2-dihydro-isoquinoline-6-yl) 2-mercapto-propionitrile; 6-(6-{3-[6-(cyano-dimethyl-methyl-polyfluoro)-sideoxy.^isoquinolin-2-yl]-2 - mercapto-phenyl}-2-mercapto-3-yloxy-2,3-di -D. Qin-4-ylamino)-#,-dimercapto-nicotinium amide; 2-[8-fluoro-2-(2-hydroxyindenyl-3-{1-methyl-5- [5-((S)-l-Methyl-fluorenyl-2-yl)-pyridin-2-ylamino]-6-o-oxy-1,6-dihydro-pyridazine-3 -yl}-phenyl)-1-oxooxy-1,2-dihydro-isoquinolin-6-yl]-2-mercapto-propanenitrile; 2-[8-gas-2-(2- Methylmethyl-5-[5-((S)-l-indenylpyrazine-3-yl)-pyridin-2-ylaminol.6-trioxy-1,6-dihydro -pyridazin-3-yl}-benzene 157475.doc -32- 201211039 yl)-1-oxooxan 2 - t; '〃-oxo-isoquinoline-6-yl]_2-mercapto-propanenitrile ;[(3 {5-[5_(2-azetidinyl-dimethyl-ethoxy)) >7<Tumentu 1 1-methyl-6-sideoxy-1 ,6-dihydro-pyridazin-3-yl}-2-oxalyl)'8-fluoro-1'-oxyl-1,2,3,4-tetrahydro-isoquinolin-6-yl] -2-mercapto-propionitrile; 2 (8 1'2_{2·Μ -3--3-(1-indolyl-5-(5-oxetan-3-yl-4'5'6) '7-tetrahydrogen than saliva [1,5·α]"pyrazin-2-ylamino)-6-oxirane-1,6-

Nitrogen _"达°秦_3-yl]-phenyl}-1-sidedoxy-1,2-dihydro-isoquinolin-6-yl)· 2-methyl-propionitrile; 6_ Second butyl·8-fluoro_2-{2-hydroxymethyl-3-[1-methyl-5-(1,·oxetane_3_yl_1,21,3',4' ,5',6'-hexahydro-[3,4']bipyridin-6-ylamino)-6-o-oxy-1,6-dihydro-pyridazine_3·ylphenyl}_2 ugly 2-oxazinone; 2-(8-fluoro-2-{2-hydroxyindenyl--[-methyl_5_(11_oxetan-3-yl-1,2',3|,4',5 ',6'-hexahydro-[3,4']-bipyridin-6-ylamino)-6-sideoxy_ι,6·dihydro-pyridazin-3-yl]-phenyl} _ι_sideoxy_i,2_dihydro-isoquinoline_6_yl)_ 2·methyl-propy; 6-t-butyl-2-{3-[5-(5-ethyl _4,5,6,7·tetrahydro-pyrazolo[ι,5_β] 0-pyridin-2-ylamino)-1-indolyl-6-o-oxy-1,6-dihydro-indole嗓_3-yl]_2_ via methyl-phenyl}-8-gas-2//"- blowing °-1-enketone; 2-(2-{3-[5-(5-ethyl- 4,5,6,7-tetrahydrogen ratio. Sit and [i,5-a]t>~_2_ylamino)-1-methyl-6-sideoxy-1,6-dihydro -Spinazin-3-yl]-2-hydroxyindolyl-phenyl}-8-fluoro-1-indolyl-1,2-dihydro-isoindole-6-yl)-2-methyl- Propiononitrile; 6-third Butyl-2-[3-(5-{5-[(lS,4S)-l-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)methyl]pyridinyl)- 2-Aminoamino}-1-methyl-6-sideoxy-157475.doc -33- 201211039 1,6-Dihydro-pyridazine-3-yl)-2-hydroxymethyl-phenyl]- 8-fluoro-2//-pyridazin-1-one; 6-t-butyl-8-fluoro-2-(2-hydroxyindole-3-{5-[5-(4-hydroxy-4-) Methyl-piperidin-1-ylmethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl _2 ugly oxazin-1-one; 4-(6-{6_[3-(6-t-butyl-8-fluoro-1-yloxy-1//-pyridazin-2-yl) -2-hydroxymethyl·styl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino}-pyridin-3-yl)-piperazine 丨-ethyl decanoate; 8-fluoro-6-(2-fluoro-1,1-dimercapto-ethyl)-2-(2-hydroxyindolyl-3-{1-methyl-5-[5 -(morpholine-4-carbonyl)- acridin-2-ylamino]-6-sideoxy-1,6-dihydro-indol-3-yl}-phenyl)_2-iso-isoline 1-ketone; 6_ second butyl '8-fluoro-2-(2-hydroxyindolyl-3-{ 1-methyl-5-[5-((lS,4S)-5-methyl-2) ,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyrazine-2-aminocarbyl]_6_ pendant oxy-1,6-monohydro-indol-3-yl}-benzene Base)-2//-azinone; 2-[8-fluoro-2-(2-oxindole) Base-3-{1•indolyl-,[,((幻-卜-methylpyrrolidin-3-yl)-pyridin-2-ylamino) 6-sideoxy-丨,6•dihydro-pyridazine_ 3 kibphenyl)-1-oxooxy-1,2-dihydro-isoquinolin-6-yl]_2-mercapto-propanenitrile; and 6-t-butyl-8-fluoro_2_( 2_ via methyl _3-{1_methyl + side oxy% [b (2,2,2-fluoroethyl)d, 2,3,,4,,5,,6,hexahydro-[ 3,4,]bipyridyl-6-ylamino]-1,6-dihydro-pyridazin-3-yl}-phenyl)_2//_pyridazine·^ ketone. The application provides a compound as described above which is used as a therapeutically active substance. The present application provides a method of treating an inflammatory condition and/or an autoimmune condition' which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula Z. 157475.doc -34 - 201211039 The present application provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. This application provides a method of treating asthma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. The application provides a pharmaceutical composition comprising a formula. The present invention provides a pharmaceutical composition comprising a compound of the formula mixed with a pharmaceutically acceptable carrier, excipient or diluent. The application provides a use of a compound of formula I for the manufacture of a medicament for the treatment of an inflammatory condition. The present application provides a use of a compound of formula I for the manufacture of a medicament for the treatment of an autoimmune disorder. The present application provides a use of a compound of formula I for the manufacture of a medicament for the treatment of rheumatoid arthritis. The application provides a use of a compound of formula I for the manufacture of a medicament for the treatment of asthma. The application provides the use of a compound as described above for the treatment of an inflammatory condition and/or an autoimmune condition. The application provides the use of a compound as described above for the treatment of rheumatoid arthritis. The present application provides for the use of a compound as described above for the treatment of asthma. The application provides a compound as described above for the treatment of an inflammatory condition and/or an autoimmune condition. The present application provides a compound as described above for use in the treatment of genital winds 157475.doc • 35· 201211039. The application provides a compound as described above for use in the treatment of a compound, method or composition as described herein. This application provides a formula I, a compound,

Wherein: R is Η, -R1, _r1_r3 or _r2_r3; R1 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally having one or more lower alkyl, hydroxy or hydroxy groups Lower alkyl, lower alkoxy, halo, nitro, amine, decyl, cyano, pendant or lower haloalkyl; R2 is -C(=0), -C( =0)0, -C(=0)NR2·, -NHC(=0)0, -C(R2')2, -〇, -C(=NH)NR2' or -S(=0)2; Each R 2 'is independently H or lower alkyl; R 3 is H or R 4 ; R 4 is lower alkyl, lower haloalkyl, lower alkoxy, amine, lower alkylamino, low carbon Alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkylheteroaryl, heteroarylalkyl, cycloalkyl, alkyl ring 157475.doc •36· 201211039 alkane , cycloalkylalkyl, heterocycloalkyl, alkylheterocycloalkyl, heterocyclic; alkyl, bicyclocycloalkyl, bicycloheterocycloalkyl, spirocycloalkyl or spirocycloalkyl, Each case is optionally subjected to one or more low carbon alkyl groups, a base, a low carbon alkyl group, a low carbon dialkyl amine group, a transbasic group, a transcarbocarbyl group, a low carbon activating group, a base group, Nitro, Amine, amidino, sulfhydryl, carbyl, pendant oxy, fluorenyl, hydroxyamino, carboxy, amine carbaryl, urethane, halo oligodeoxy or dentate The carbon-burning group is substituted, wherein two low-carbon yard groups can form a ring together; Y4 is Y4a, Y4b, and 丫4. Or Y4d; Y4m or halogen; Y4b is a low carbon alkyl group as the case may be substituted by one or more groups selected from the group consisting of low carbon halogen groups, dentate, hydroxyl group, amine group, cyano group and low carbon alkoxy group Substituent; Y4e is a lower alkylcycloalkyl group as the group consisting of one or more selected from the group consisting of a lower alkyl group, a lower carbon alkyl group, a hydroxyl group, a hydroxyl group, an amine group, a cyano group and a lower alkoxy group Substituent substituted; and Y is an amine group 'optionally substituted with one or more lower alkyl, alkoxy lower alkyl or hydroxy lower alkyl; or a pharmaceutically acceptable salt thereof. In a variation of formula Y, Y4 is a third butyl group, a dimethylamino group, a cyclopropyl group or an isopropyl group. In a variation of the formula, Y4 is a third butyl group. In a variation of the formula ’, Y4 is a dimethylamino group. In a variation of the formula ’, Y4 is a cyclopropyl group. 157475.doc -37. 201211039 In a variation of formula r 'Y4 is isopropyl. In a variation of formula ’, 'R is -W-R3; Ri is benzylidene; r3 is R4; and R4 is heterocycloalkyl optionally substituted by lower alkyl. In a variant of formula I, R is -Ri-R2-R3; R丨 is 0-pyridyl; r2 is -C(CH3)2; R3 is R4; and ^4 is optionally one or more a lower alkyl substituted lower alkylamino group, a lower a carbon dialkylamino group or a heterocyclic alkyl group. In a variation of the formula ', 'R is -R1-R2-R3; R1 is phenyl or pyridyl; R2 is -C(=0), R3 is R, and R4 is as appropriate - or a plurality of low The carbon-burning base replaces the lining or the mother. In a variation of the formula, R1 is . Ritudinyl; R3 is R4; and R4 is -S(=0)2R4_, wherein R4' is lower alkyl.

Among them, ruthenium, dentate, low carbon burnt or low carbon functional base. In a variant of the formula, γ4 is

Wherein Y5 and Y6 are independently hydrazine, lower alkyl or lower haloxyalkyl. In a variant of the formula, γ4 is

V wherein Υ5 and Υ6 are independently hydrazine or lower alkyl. In a variant of the formula, Υ4 is 157475.doc 201211039 *

Wherein γ5 and γ6 are independently H, lower alkyl or lower haloalkyl. In a variation of the formula ,, Y4 is a third butyl group; R is _R1_R3; R1 is a ratio of a bite base; R3 is R4; and R4 is -S(=〇)2R4·, wherein R4 is a lower alkane Base 0 In a variation of the formula γ, γ4 is the third butyl group; the ruler is _R1_R2_R3; • R1 is. Ritudinyl; R2 is _C(CH3)2; R3 is R4; and R4 is a lower alkylamino, lower dialkylamino or heterocyclic ring optionally substituted with one or more lower alkyl groups. Alkyl in a variant of the formula YY4 is a third butyl group; R is -R^-R^R3; 1^ is a pyridine group; R2 is _C(=0); R3 is R4; R4 is morpholine or piperazine which is optionally substituted with one or more lower alkyl groups. In a variation of the formula, Y4 is a third butyl group; the ruler is _ri_r3; the ruler 1 is a bite base, R is R, and R4 is a heterocyclic ruthenyl group optionally substituted with a lower carbon group. The present application provides a compound of formula 1' selected from the group consisting of: 6-dibutyl-2-(3-{5-[5-(l-ethylamino)-l-methyl-ethyl) _吼. 定_2-Aminoamino]-1-indolyl-6-sideoxy-1,6-dihydro-calli _3_kib 2-methyl-phenyl)-8-fluoro -2ΑΓ-β太嗓-1-one; 6-second butyl-8-gas- 2-(2-methyl-3-{1-mercapto_5-[5-(? - number base) - ° ratio bit-2-ylamino group]-6-sideoxy-1,6-dihydro-health. Qin_3_yl}-phenyl)_ 2 仏 blowing. Qin-1-one; 6-t-butyl-8-fluoro-2-{2-hydroxymethyl_3-[5_(5-曱石石黄醯基_pyridine_ 157475.doc -39- 201211039 2- base Amino)-1-indolyl-6-tertiaryoxy-1,6-diaza-indolyl-3-yl]-phenyl}-2 //- ° too σ Qin-1 - sun, 6- Third butyl-8-^-2-(2-fluorenyl-3-{5-[5-(3-indolyloxy-acetonyl-1-ylmethyl)-° ratio π -2-ylamino]-1-methyl-6-o-oxy-1,6-diaza-kind-3-yl}-epi)-2 σ太嘻-1 -copper, 6 - Dibutyl-8-gas_2-(2- mercapto-3 - {1-indolyl-5-[5-(8-mercapto-3,8-diaza-bicyclo[3.2.1] Oct-3-ylindenyl)-acridin-2-ylamino]-6-hydroxyl-1,6-diaza-salt-3-yl}-phenyl)-2 //-. Tooqin-1, 6-t-butyl-2-(3-{5-[5-(2-dimethylamino-1,1-dimethyl-ethoxy)-. 〇 -2 - -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 2 . Taiqi Qin-1 - 酉, 2-{3-[5-(5-azetidin-1-ylindolyl-pyridin-2-ylamino)-1-methyl-6-side oxygen Base-1,6-diaza-violation. Qin-3-yl]-2-pyridyl-phenyl}-6-t-butyl-8-fluoro-2//-pyridazin-1-one; 6-t-butyl-2-{3 -[5-(5-diodecylaminoindolyl-acridin-2-ylamino)-1-indolyl-6-yloxy-1,6-diaza-viol-methyl-3-yl ]-2-carboxylidene-phenyl b-fluoro-p-pyridazin-1-one; 6-t-butyl-2-(3-{5-[(111,58)-5-(3) ,8-diaza-bicyclo[3_2_1]oct-8-yl)-° ratio of -2-ylamino]-1-indolyl-6-sideoxy-1,6-diaza-heal Qin-3-3-yl}-2-thiol-based)_8-gas-2Η-σΑ σ秦-1 -嗣, 6-{6-[3-(6-t-butyl-8-fluoro- 1-Phenoxy-1Η-pyridazin-2-yl)-2-hydroxymethyl-phenyl]-2-mercapto-3-yloxy-2,3-dihydro-pyridazin-4-yl Amino}-oxime, fluorene-dimercapto-nicotinium amide; and 6-t-butyl-8-fluoro-2-{2-hydroxyindolyl-3-[1-indolyl-6-side oxygen Base-5-(5- 157475.doc •40- 201211039 difluoromethyl-°pyrazin-2-ylamino)_ι,6_dihydro-pyridazine_3_yl]phenyl brom 2h_ 1-ketone. The present application provides a method of treating an inflammatory condition and/or an autoimmune condition comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound. The application provides a method of treating arthritis comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound of the formula. The application provides a method of treating asthma comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound of Formula 1'. The application provides a method of inhibiting B cell proliferation comprising administering to a patient in need thereof a therapeutically effective amount of a Btk inhibitor compound of the formula </ RTI>. The present application provides a method of inhibiting Btk activity comprising administering a Btk inhibitor compound of any of the formulas, wherein the Btk inhibitor compound exhibits a concentration of 5 micromoles or 5 in an in vitro biochemical assay of Btk activity. IC5 below the micromolar concentration. . In a variation of the above method, the Btk inhibitor compound exhibits an IC5Q concentration of 100 nanomolar or less than 100 nanomolar in an in vitro biochemical assay of Btk activity. In another variation of the above method, the in vitro biochemical assay of the compound at Btk activity exhibits an IC50 of 10 nanomolar or less than 10 nanomolar. The present application provides a method of treating an inflammatory condition comprising co-administering a therapeutically effective amount of an anti-inflammatory compound in combination with a Btk inhibitor compound of Formula 1, in a subject in need thereof. 157475.doc • 41 · 201211039 The present application provides a method of treating arthritis comprising co-administering a therapeutically effective amount of an anti-inflammatory compound in combination with a Btk inhibitor compound of the formula in a patient in need thereof. The present application provides a method of treating lymphoma or BCR-ABL leukemia cells by administering a therapeutically effective amount of a Btk inhibitor compound of formula I to a patient in need thereof. The present application provides a pharmaceutical composition comprising a Btk inhibitor of the formula. The mixture is admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

The present application provides a use of a compound of the formula for the manufacture of a medicament for the treatment of an inflammatory condition. This application provides the use of a compound of the formula , for the manufacture of an agent for the treatment of an autoimmune disorder. The application provides a compound, method or composition as described herein. Examples of representative compounds encompassed by the present invention and within the scope of the present invention are provided in the undergarment. Provide such examples and (4) preparations to familiarize

The invention is to be understood and carried out more clearly. It should not be considered as a scope of the invention, but only the description and representation of the invention. - Generally speaking, the name used in the case is based on 4〇) auT 〇NOMTM 'is also used to generate mpAc system naming ^ 丨 ' = = there is a contradiction between the structure, the structure depicted corresponds to more weighting;; right structure or structure - part of the stereochemistry m such as thick "no" The structure or part of the structure is to be understood to cover the stereoisomers of the I57475.doc-42·201211039. Table I describes examples of pyridazinone compounds according to formula I: Table I.

Compound nomenclature 1-1 6-tert-butyl-2-(3-{5-[5-(1-ethylamino-1-methyl-ethyl)-pyridin-2-ylamino] -1-mercapto-6-sideoxy-1,6-diaza-indan-3-yl}-2-methyl-phenyl)-8-gas-2//· Ketone 1-2 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{ 1 -fluorenyl-5·[5-(吗喻-4-罗炭基)-D ratio σ定-2-ylamino]-6-o-oxy-1,6-di-r-indole-3-yl}-phenylpyridazin-1-one 9 1-3 6-t-butyl- 8-fluoro-2-{2-hydroxyindolyl-3-[5-(5-methylpyrenethiol-0-biting-2-ylamino)-1 -indolyl-6-yloxydiazepine -Dal-3-yl]-phenyl} -2//· ° too σ Qin_1 -嗣〇=|=〇157475.doc 43- 201211039 1-4 6-Third butyl-8-fluoro- 2-(2-methyl-3-{5-[5-(3-indolyl-azetidin-1-ylindenyl)-0-biti-2-ylamino]-1- Mercapto-6-o-oxy-1,6-diaza-indolyl-3-yl}-phenyl)-2 from ketone-1-one

1-5 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{l-fluorenyl-5-[5-(8-fluorenyl-3,8-diaza-- Bicyclo[3.2.1]oct-3-ylindenyl)-.pyridin-2-ylamino]-6-o-oxy-1,6-diaza-contained 桊-3-yl}-phenyl Pyridazine-1-one

1-6 6-t-butyl-2-(3-{5-[5-(2-didecylamino-1,1-didecyl-ethoxy)-0 ratio. Aminoamino]-1-mercapto-6-o-oxy-1,6-di-milk-yttrium-3-yl}-2-hydroxyindolyl-phenyl)-8-It-2//·° Too small ketone

157475.doc 44- 201211039

1-7 2-{3-[5-(5-azetidin-1-ylmethyl-~biti-2-ylamino)-1-methyl-6-oxirane-1, 6-Dihydro-pyridazin-3-yl]-2-hydroxyindolyl-phenyl}-6-tert-butyl-8-gas-2//-blowing. Qin-1-one °γ%ΗΝ 1-8 6-Tertibutyl-2-{3-[5-(5-dimethylaminomethyl-pyridin-2-ylamino)-1-methyl -6-o-oxy-1,6-diaza-indolyl-3-yl]-2-carboxylidene-phenylpyridazin-1-one °Yy〇s\ °rI9r^ 1-9 6 -T-butyl-2-(3-{5-[(lR,5S)-5-(3,8-diaza-bicyclo[3.2.1]oct-8-yl)-acridin-2- Aminoamino]-1-methyl-6-oxyl-1,6-dihydro-d-heptyl-3-yl}-2-carboxyl-phenyl)-8·gas-2Η-σ&gt; ^σ桊-1-ketone.秘马 jTVNH 1-10 6-{6-[3-(6-Tert-butyl-8-fluoro-o-oxy-1Η-β-t-but-2-yl)_ 2-hydroxyindolyl-phenyl] -2-Methyl-3-oxooxy-2,3-dichloro-gumohyl-4-ylamino}-indole, indole-dimercapto-nicotinamide 157475.doc 45- 201211039 6- Third butyl-8- defeat-2-{2-methyl-3-[l-fluorenyl-6-oxo-1-11 5-(5-trifluorodecyl-»bisazine-2 -ylamino)-1,6-dihydro-. Daazin-3-yl]-phenyl}-2H-phthalazin-1-one

1-12 6-Tertibutyl-8-gas-2-(3-{5-[5-(2-yl-1,1-didecyl-ethoxy)-pyridin-2-ylamine ]]-1-meryl-6-sideoxy-1,6-diaza-hetero 0-methyl-3-yl}-2-carboxylidene-phenyl)-2//-°Taiqin-1 -ketone

Λ ΟΗ

1-13 2-(3-{5-[5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)·deuterium ratio. ]-1-fluorenyl-6-sideoxy-1,6-diox_viol-qin-3-yl}-2-hydroxyindolyl-phenyl)-6 second butyl-8·gas-2 //-blow. Qin-1-陋

Α Νϋ 1-14 6-Second-butyl-8-fail-2-(2-pyridyl-3-{5-[5-(2-hydroxy-2-methyl-propoxy)-° ratio定-2-ylamino]-1-indolyl-6-o-oxy-1,6-diaza-indol-3-yl}-styl)-27/-pyrazine-1-one

ΟΗ

157475.doc 46- 201211039

1-15 1-16 1-17 1-18 2·[8-fluoro-2-(2-hydroxymethyl-3-{l-fluorenyl-5-[5·(?琳·4-) -0 is more than 2-aminoamino group]-6-sideoxy-1,6-diaza-callicyl-3-yl}-phenyl) small pendant oxy-1,2.diaza-iso喧琳-6-yl]-2-mercapto-propanoid 6-t-butyl-8·fluoro-2-(3-{5-[5-((S)-2-hydroxy-3-methoxy) --propoxy)-D ratio benzyl-2-ylamino]-1-indenyloxy-1,6-diaza-indolyl-3-yl}-2-thiol-phenyl) -2//- blowing 17 Qin-1 -Cong 6-t-butyl-8-fluoro-2·(3-{5-[5-((R)-2-hydroxy-3-indolyl--- Oxy)-indole-2-ylamino]-1-indolyl-6-yloxy-1,6-diaza-septazin-3-yl}-2-carboxylidene-phenyl)- 2//-Blowing ketone-1-keto 6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3-{l-fluorenyl-5-[5-((S)-l- Methyl-pyrrolidine-di-2-yl)-.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2//~. Too-1-ketone

Palm

Pair of palm HO

157475.doc • 47· 201211039 1-19 6-Ter Butyl-8-fluoro-2-(2-hydroxydecyl-3-{l-fluorenyl-5-[5-((R)-l- Methyl-0-Bile-2-yl)-D ratio 0^-2-ylamino]-6-sideoxy-1,6-dihydro-vio. Qin_3_yl}-stupyl) -2//~ oxazin-1-one °tV°i ΗΝ human into φ &quot; ότ 1-20 6-{6-[3-(6-t-butyl-8-H-1 - pendant oxy group -1//&quot; ° too. Qin-2-yl)· 2-methyl-phenyl]-2-mercapto-3-yloxy-2,3-dihydro-pyridazin-4-yl Aminodifluorenyl-nicotine decylamine °YN'rP〇vl φ u &quot; Ο丄Iji〆1-21 6-t-butyl-8-fluoro-2-(2-hydroxydecyl-3-{ 5-[5·(4-Pyano-4-methyl-slightly aceto-1 -indolyl)-α ratio 2 -ylamino]-1-indolyl-6·sideoxy-1,6 -dihydro-pyridazin-3-yl}-phenyl)-2/f-oxazin-1-one y ^[-〇Η 1-22 6-t-butyl-8-fluoro-2-(2 - via methyl-3-{l-methyl-5-[5-(6-methyl-2,6-diaza-spiro[3.3]hept-2-yl)-. Amino group]-6-sideoxy-1,6-diaza- shouting. Qin-3-yl}-phenyl)-2//- blowing σ Qin-1 - class V ΐ

157475.doc • 48 - 201211039

1-23 6-Tertibutyl-2-{3-[5-(5-Ethylene-branched-to-bit-2-ylamino)_1-indolyl-6-sideoxy-1 ,6-diaza-.oxazin-3-yl]-2-hydroxydecyl-phenyl}-8-fluoro-2/ί·Blowing 嗓-1-嗣Yi r0%-YY^ Λ ^ ° F 0 =1=0 1-24 6-Tertibutyl-8-fluoro-2-(2-hydroxyindolyl-3-{1-methyl-6- pendantoxy-5-[5·(propyl- 2-Stone 基 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- °rK hi?^WvV φ υ ° F 0=|=0 1-25 6-Ter Butyl-8-fluoro-2-(3-(5-[5-(2-hydroxy-ethylthio)) -° ratio bite · 2 · arylamino group - 1 -methyl-6 · pendant oxy-1,6-dihydro-hetero. Qin-3-yl}-2-hydroxyindolyl-phenyl)-2 From pyridazine-1-one Υι φ υ.f ΟΗ 1-26 6-t-butyl-8-fluoro-2-(3-(5-[5-(2-3⁄4 base- 乙) -°Bite-2-ylamino]-1-methyl-6. oxo-1,6-diar-arsen-3-yl}-2-hydroxymethyl-phenyl)-2/ /-pyridazine-1_ketoneΥι γ°^^Λ ^ 〇F o=s=os OH 157475.doc 49- 201211039

157475.doc 50- 201211039

1-30 6-Tertibutyl-2-{3-[5-(1·-ethyl-1·,2,,3',4,5|,6'-hexahydro-[3,4 ']L's α-Bist-6-ylamino)-1-methyl-6-o-oxy-1,6-dihydro-indol-3-yl]-2-indolyl-stupyl}- 8-气-2//~吹0秦-1-嗣°τΎ°ι ΗΝΛ^νγΝγν γ&quot; 1-31 6-Tertibutyl-2-{3-[5-(1,5-dimethyl -1 from p-azol-3-ylamino)-1-methyl-6-o-oxy-1,6-diaza-adalyl-3-yl]-2-methyl-phenyl}- 8-Fluorine.太°秦-1 -嗣°ϊΎ°ι hn^vvnyV r\ 1-32 6-Ter Butyl-8-fluoro-2-(2-hydroxydecyl-3-{1-decyl-5-[ 5-((S)-l-methylpyrrolidin-3-yl)-pyridin-2-ylamino]-6-tertiaryoxy-1,6-dihydro-form. Qin-3-yl} -Phenyl)-2//. Taizin-1-one °τΤι X 1-33 6-Second butyl-8-gas-2-(2-methyl-3·{1-methyl-5-[5-((R)-) l-Methyl-D is 嘻. -3--3-))-D ratio bite 2_ylamino]-6-sideoxy-1,6-diaza-darin-3-yl}-phenyl) -2//- oxazin-1-one °τΎ°ι, 157475.doc -51 - 201211039 1-34 6-Tertibutyl-8-fluoro-2-{2-hydroxyindolyl-3-[1 -mercapto-5-(4-mercapto-3,4,5,6-tetrahydro-2//-[1,2']bipyridinium-51-ylamino)-6-sideoxy -1,6-diaza-viol-qin-3-yl]-phenyl}-2//-°太嘻-1 -嗣Ny ^ ° F 0 1-35 6-t-butyl-2-{ 3-[5-(5-Cyclobutylaminoindolyl-° σQin-2-ylamino)·1·indolyl-6-ί-yloxy-1,6-diazo-3⁄43⁄4 嘻-3 -yl]-2-thiol-phenyl}-8· defeat-2//. Too-1_ketone〇丫\r°VYY^ N&lt;sJ ΗΝ*^ &lt;&gt; 1-36 6-Tertibutyl-2-(3-{5-[5-(2-didecyl) Amino-ethoxy) ° 嗓 基-2-ylamino]-1-methyl-6- oxirane-1,6-diaza-indole 11 Qin-3-yl}-2-hydroxyl -Phenyl)-8-fluoro-2//-呔°-Hin-1-one °YN'if r0]%&lt;ifwV Ny ^ ° F 〇] V 1-37 6-Third-butyl-8- Gas-2-(2- mercapto-3-{1-mercapto-5-[5-(4-indolyl). °*&quot;2-based Amino]-6-sideoxy-1,6-diaza-violent σ-yl-yl}-phenyl)-2//-σ 嗓-1·ketone °r\ 4,

157475.doc ·52· 201211039

1-38 6-Tertibutyl-2-(3-{5-[5-(2-dimethylamino-1,1-didecyl-ethoxy)-α-pyrimidin-2-yl Amino]-1 -mercapto-6-o-oxy-1,6-diphos-darsin-3-yl}-2-indolyl-phenyl)-8-fluoropyridazine-1-_ °r\ Ny ^ ° FX 1-39 6-Tertibutyl-2-(3-{5-[6-(2-didecylamino-1,1-dimethyl-ethoxy)-嗔-3-ylamino]-1-indolyl-6_sideoxy-1,6-diqi-azino-3-yl}_2-fluorenyl-phenyl)-8-fluoro- 2//·Blowing small ketone y V 1-40 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(1-曱) --piperidin-4-yl)-pyridazin-3-ylamino]-6-sideoxy-1,6-two wind-to ° Qin_3 -yl}-phenyl blowing ° Qin-1- Ketone V'n HN Renren Bu ^ ^ 〇? ΐ 1-41 6-Ter Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-indolyl-5·[5-( 4-fluorenyl-succinyl-1-ylindenyl)-indenyl-2-ylamino]-6-o-oxy-1,6-diaza-enrich-3-indenyl-phenyl blowing °秦-1-调0rVVr9^ I7uN^ V 〇, 157475.doc •53- 201211039 1-42 6-Tertibutyl-8-fluoro-2-[2-hydroxyindolyl-3-(5-{5 -[(2-decyloxy-ethylamino)-indenyl] butyl 2-amino-amino-I-mercapto-6-sideoxy 1,6-dihydro-inert-3-yl )-phenyl]-2 //*Blowing Qin

6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3-{1·indolyl-5-[5-((lS,4S)-5-methyl-2,5-di) Nitrogen 1-43 hetero-bicyclo[2.2.1]hept-2-ylindenyl)-° ratio -2-ylamino]-6-sideoxy-1,6-diaza-violation-11 Qin-3 -yl}-phenyl)-2//-pyridazine-butanone

1-44 6-Ter Butyl-8·Gas-2-{2-Methyl-3·[5_(5-{[(2-Methoxy-ethyl)-indenylamino]- Mercapto}-° ratio sigma-2-ylamino)-1-indolyl-6-o-oxy-1,6-diaza-darin-3-yl]-phenylpyridazin-1-one

157475.doc 54- 201211039

1-46 1-48 6-Tertibutyl-8-fluoro-2-(2-hydroxyindolyl-3-{l-fluorenyl-5-[6-(4-indolyl--D-Q--1) -yl)-daind-3-ylamino]-6-sideoxy-1,6-diaza-vioran-3-yl}-styl)-2//*11 toco-1-one 6-Secontabutyl-8-gas-2-(2-3⁄4 methyl-3-{1-indolyl-5-[6_((lS,4S)-5-fyl-2,5-diaza) Hetero-bicyclo[2.2.1]heptan-2-yl)dain-3-ylamino]-6-sideoxy-1,6-di-serum-slit-hom-3-yl}-phenyl)- 2/ί-oxazin-1-one 2-(3-{5-[5-(azetidin-1-yl))pyridin-2-ylamino]phosphonium-6-side oxygen Base-1,6-dihydro-septazin-3-yl}-2-hydroxymethyl-phenyl)-6-tert-butyl-8-fluoro-2//-pyridazin-1-one 6- Third butyl·2-(3·{5-[5-(1,1 ·di- oxy-1 λ6-thio- phenanthyl-4-yl)-°-pyridin-2-ylamino group] -1-mercapto-6-sideoxy-1,6-dihydro-darin-3-yl}-2-sulfonyl-stupyl-8-gas-2//·σ too D- Qin Ketone

157 157475.doc -55- 201211039 6-Ter Butyl-8-fluoro-2-(2-hydroxymethyl-3-{l-fluorenyl-5-[5-(2-oxa-6-nitrogen) Hetero-spiro[3.3]heptane-6-carbonyl)-° than chito-2-ylamino]-6-sideoxy-1,6-diazada. Qin-3-yl}-stupyl)- 2//-pyridazine-1-one

6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{l-fluorenyl-5-[5-(6-fluorenyl-2,6-diaza-spiro[3.3] Heptane-2-rebase)-.t-but-2-ylamino]-6-o-oxy-1,6-diaza-indolyl-3-yl}-phenyl)-2/ /-pyridazine-1-one

6-{6-[3-(6-Tert-butyl-8-fluoro-1_sideoxy-1 tablet~°T-methyl-2-yl)-2-hydroxymethyl-phenyl]-2 -methyl-3-yloxy-2,3-diaza-indol-4-ylamino}-indole 2-didecylamino-ethyl)-nicotinamide

6-{6-[3-(6-Tert-butyl-8-fluoro-b-oxyl-1//-.t.hom-2-yl)-2-hydroxyindolyl-phenyl]-2 -mercapto-3-oxooxy-2,3-diar-pyridazin-4-ylamino}--V-(2-trans-ethyl-ethyl)-iV-mercapto-nicotinamide

OH 157475.doc -56- 201211039

1-53 l-(6-{6-[3-(6-Tertibutyl-8-fluoro-1-indolyl-1//·pyridazin-2-yl)-2-methyl- Phenyl]-2-methyl-3-oxooxy-2,3-diaza-enazol-4-ylamino-3-yl-3-yl)-azetidin-3·carbonitrile 0γΝ ρΡ〇Ν] OF 9 1-54 6-Tertibutyl-8-fluoro-2-(2-hydroxyindolyl-3-{5-[5-(3-)-based-σ ratio -1-184 Alkyl)-11-biti-2-ylamino]_1_mercapto-6-sideoxy-l,6-diaza-darin-3-yl}-phenyl)-2//.pyridazine -1-ketone 0γΝ'ρΡ〇ν| 0 F 9 0 ^^-OH 1-55 6-Second butyl-8·like j-2-(2-methyl-3-{5-[5- (4-Hydroxy-piperidine carbonyl)-pyridin-2-ylamino]-1-methyl-6- oxo-1,6-dihydro-darin-3-yl}-phenyl hydrazine -1_ketone 0丫NfO hiA^y^vV O^N^| 1-56 6-Ter Butyl-8-fluoro-2-(2-hydroxymethyl-3-{l-methyl-5- [5-(4-indolyl-2-bottom-methyl-1-yl)_°Bite-2-ylamino]-6-sideoxy-1,6·diaza-enhanced _ 3 -yl} -phenyl)_ 2/f-blow-1-one V 0 N 1 157475.doc 57- 201211039 1-57 6-Tertibutyl-2-(3-{5-[5-((S) -l,2-dihydroxy-ethyl)-.pyridin-2-ylamino]-fluorenyl-f-yl-6-tertiaryoxy-1,6-diaza-chiral-3-yl}-2 · Mercapto-phenyl)-8, fluorine-2/f·Blowing γ 11 ΗΟ^) HO 1-58 2-{3-[5-(5-azetidin-1-yl-mercapto-1-indolyl-1//-° ratio °-3-aminol group -1·decyl-6-sideoxy-1,6-diqi-enriched qin-3-yl]-2-pyridyl-phenyl}-6-t-butyl-8-fluoro- 2//-Blowing ketone-1-ketone 卜Bu D 1-59 6-Third butyl-8-|t-2-{2- fluorenyl-3-[l-fluorenyl-5-(5- Mercapto-4,5,6,7-tetrahydro-σ ratio. Sit and [1,5-β] ° ratio ° Qin-2-ylamino)-6-sideoxy-1,6-di - 嘻-3-yl]-phenyl}-2//~ 吹σ秦-1 -嗣ή... 〆1-60 6-T-butyl-8-氤-2-{2-hydroxymethyl group 5--5-oxetan-3-yl-4,5,6,7-tetrazole-° ratio 0[1,5-α]° ratio. Qin-2-ylamino group )-6-Sideoxy-1,6-diaza-. ° °-3--3-yl]-phenyl}-2//-β太嗓-1-one b I57475.doc 58- 201211039

1-61 6-Tert-butyl-8-fluoro-2-{3-[5-(1,,2,,3,,4,,5|,6'-hexahydro-[3,4'] 〇 〇 比 bit-6-ylamino)·1-mercapto-6-sideoxy-1,6-diaza-darin-3-yl]-2-hydroxyindolyl-phenyl}-2 private Hey. Indole-1-one jPynh HN^ 1-62 6-tert-butyl-8-fluoro-2-{2-hydroxyindolyl-3-[5-(Γ-曱烧醯基-1', 2' ,3',4',5',6|-hexahydro-[3,4|] °°°-6-ylamino)-1-methyl-6-sideoxy-1,6- Dihydro-indol-3-yl]-phenylpyridazin-1-one l 1-63 2-{3-[5-(r-Ethyl-1|, 2', 3', 4|, 5|,6'-hexahydro-[3,4']-linked u-biti-6-ylamino)-1-methyl-6-oxirane-1,6-diaza-violet-3- Methyl-2-phenyl}-6-tert-butyl_8_fluoro-2//-pyridazin-1-one j^YNH ΟγΝ^Ι 1-64 6-second butyl- 8-gas-2·{2- via methyl-3·[5-(4-pyridyl-4-mercapto-3,4,5,6-tetrahydro-27/-[1,3,] The ratio of -6-aminoamine-1-methyl-6-hydroxyl-1,6-dihydro-d. Qin-3·yl]-phenyl}-2/ί-pyridazine-1·one fYNH 1 HO^ 157475.doc 59- 201211039

1-65 6-Second-butyl-8-gas-2-{2-methyl-3-[5-(4-hydroxy-3,4,5,6-tetrahydro-2//-[1 ,3']bipyridyl-6'-yl-urethano)-1-indolyl-6-o-oxy-1,6-diaza-vio-hypo-3-yl]-phenyl}-2// -°太嘻-1-keto o^Yho^ frNH HO^^1 6-Ter Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-indolyl-5-[5- ((lR,5S)-3-mercapto-3,8-diaza 1-66 hetero-bicyclo[3.2.1]oct-8-yl)-.biti-2-ylamino]-6-side Oxy-1,6-diaza-yield.hom-3-yl}-benzoquinone jfYNH group)-27/-°tol-1-one 6-t-butyl-8- defeat-2-{2 - mercapto-3-[1-mercapto-5-(Γ-曱-l-67 1', 2',3,,4,5,6'-hexahydro-[3,4' ] Associated O HO pc into mw 1 ° ratio ° -6-aminol)-6-sideoxy-1,6-diaza-indan-3-yl]phenyl}-2//- blowing.桊-1 -嗣JJ 6-t-butyl-2-(3-{5-[1- 〇丫Ν,1?Η〇Ί((R)-2,3-dihydroxy-propyl)-1 //- 1-68 pyrazol-3-ylamino]-1-methyl-6-tertiaryoxy-1,6-diaza-iso-qin-3-yl}-2-methyl-benzene Base)-8-gas- 2//- blowing °-Hin-1-one OH OH 157475.doc 60 · 201211039

1-69 6-Tertibutyl-2-(3-{5-[5-(4-ethyl-pyrene)-σ ratio bit-2-ylamino]-1-indolyl-6- The pendant oxy-1,6-diaza-d.hom-3-yl}-2-fluorenyl-phenyl)-8-gas-2//-. Tooqin _ 1-keto V ϋ 1-70 6-t-butyl-8-^-2-(2-light methyl-3-{5-[1-(2-)-yl-2-methyl -propyl)-1//-oxazol-3-ylamino]-1-indolyl-6-yloxy-1,6-dihydro-indol-3-yl}-phenyl)-2呔° Qin-1-ketone bird 1-71 2-(8-fluoro-2-{2-hydroxyindol-3-[1-indolyl-5-(1Λ曱-yl-1'52',3 ',4|,5',6|-hexahydro-[3,4|]-linked ratio -6-ylamino)-6-sideoxy-1,6-difeng-d. Qin-3 -yl]-phenyl}-1-olyloxy-1,2-diaza-isowa scare_6·yl)-2·methyl-propanoid °υν'νη〇^ι ογΜ X 1-72 2 - (2-{3-[5-(5-azetidin-1-ylmethyl-1-indenyl-1//-pyrazole-3-ylamino)-1·indolyl-6 -Sideoxy-1,6-dihydro-pyridazin-3-yl]-2. fluorenyl-phenyl b- 8-fluoro-1-yloxy-1,2-di-iso-indiyl- 6-base) _ 2-mercapto-propy guess, Fyj! °γΝ/0^ °χχ Λν ^ Q 157475.doc -61- 201211039 1-73 2-[2-(3-{5-[5-( 2-azetidin-1-yl-, 1-dimercapto-ethoxy)-.t-but-2-ylamino]-1-methyl-6-oxirane-1, 6-diaza-vioron-3-yl}-2_methyl-phenyl)-8-aero-1 -trioxy-1,2-diaza-isoindolin-6-yl]_2-曱基-丙猜,FrJ® HO. HN Into 1-74 2-(8-fluoro-2-{2-hydroxymethyl-3-[l-fluorenyl-5-(5-mercapto-4,5,6,7-tetrahydrogen. And [1,5-α]° 嘻 嘻-2-ylamino)-6-sideoxy-1,6-diaza-d. Qin-3-yl]-phenyl}-1-sideoxy -1,2-diaza-isoindole-6*yl)·2-mercapto-propionate 6-(6-{3-[6-(cyano-dimethyl-methyl)-8- Fluor-1-oneoxy-1//- ΟγΝ. ΗΟ 〇γ^γ 1-75 iso-σ quinolin-2-yl]-2_ fluorenyl _ abbreviated hnJ〇vVn^ yl}-2-methyl -3-Sideoxy-2,3-diaza-indole 13 Qin-4-ylamino WW-dimercapto-nicotinamide 丄〒〆 157475.doc 62 · 201211039 1-76 2-[8 -^-2-(2-pyridyl-3-{l-methyl-5-[5-((S)-l-methyl-Bilo-2-yl)-Dtb-But-2-ylamine -6-Sideoxy-1,6-diaza-enoxa-3-yl}-phenyl)-1_sideoxy-1,2-dimur-isoindolin-6-yl]- 2-mercapto-propiononitrile

1-77 2-[8-fluoro-2-(2-pyridyl-3-{l-methyl-5-[5-((S)-l-fluorenyl-吼p each bit-3) )-°Bite-2-ylamino]-6-sideoxy-1,6·dihydro-indol-3-yl}•stupyl)-1·Sideoxy-1,2-dihydrogen -isoquinolin-6-yl]-2.methyl-c-cause

2-[2-(3-{5-[5-(2-azetidin-1-yl-1,1-diindolyl-ethoxy)-σ ratio-2-ylamino] -1-mercapto-6-o-oxy-1,6-di-rhenyl-trim-3-yl}-2-carboxylidene-phenyl)-8.-1--1-oxy-1,2 , 3,4-tetrazine-isoindolin-6-yl]-2-mercapto-propionitrile.

°&gt;cv 157475.doc 63- 201211039 1-79 2-(8-Fluoro-2-{2-hydroxymethyl-3-[l-fluorenyl-5-(5-oxetan-3- Base-4,5,6,7-tetra-argon ratio 嗤[1,5-α] oxazin-2-ylamino)-6-sideoxy-1,6-di---11 桊-3 -yl]-phenyl}-1-sidedoxy-1,2·diaza-isoindolin-6-yl)-2-indolyl-propionitrile: ά^99^Ν ή 1-80 6- Tributyl-8-fluoro-2-{2-hydroxyindol-3-[1-indolyl-5-(anthracene-oxetan-3-ylhexanitro-[3,4'] beta Than 6-ylamino)-6-o-oxy-1,6-dihydro-indole-methyl-3-yl]-phenyl}-2//-°tol-1-one oxime ν ^ ο f Λ ο 1-81 2-(8-fluoro-2-{2-hydroxyindolyl-3-[1-methyl-5-(anthracene-oxetan-3-yl-1·,2· ,3|,4·,5·,6'-hexahydro-[3,4']bipyridin-6-ylamino)-6-clavyl-1,6-diaza-violent sigma-3 -yl]-phenyl-oxy-1,2-diaza-isoindolin-6-yl)-2-indenyl-propanenitrile °ΥΝ'Ν Ο

157475.doc 64- 201211039

1-82 6-Tertibutyl-2-{3-[5-(5-ethyl-4,5,6,7-tetrahydro-leaf sputum and [1,5-〇]°°° Qin-2-ylamino)-1-indolyl-6-o-oxy-1,6-dihydro- hydrazin-3-yl]_2-pyridyl-phenyl}-8-fluoro-2/ /-β太嘻-1- Ketone V^VynyV Λν ^ 0 ^ 0 1-83 2-(2-{3-[5-(5-ethyl-4,5,6,7·tetrahydro-. °Sit and [l,5-a]D is more than indole-2-ylamino)-1-indolyl-6-sideoxy-1,6-diaza-indolyl-3-yl]-2- Mercapto-phenyl}-8-don-1-yloxy_1,2_diaza-isoindolyl-6-yl)-2-mercapto-propionate t... t 1-84 6-third Butyl-2-[3-(5-{5-[(lS,4S)-l-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)methyl]) 2-aminoamino}-1-indolyl-6-tertiaryoxy-1,6-diaza·d-Chloro-3-yl)-2-hydroxymethyl-phenyl]-8-fluoro-2 Blowing 嗓-1-_ 〇γ^ΝΗΟχ ογ0^ φκ Η 1-85 6-Second butyl-8-gas-2-(2-methyl-3-{5-[5·(4-hydroxy-) 4-mercapto-Brigade bite-I-ylmethyl)-°Bite-2-ylamino]Bistyl-6-sideoxy-1,6-di-r-indole-3-yl}- Phenyl)·2//~ 口太嘻-1,嗣Ο^Ν,ΗΟ Ν^γ%Λ- U\〇H 157475.doc -65- 201211039 1-86 4-(6-{6-[3 -(6·T-butyl-8-fluorosmall pendant oxy-1//·pyridazine -2-yl)-2-carboxylidene-phenyl]-2-mercapto-3-yloxy-2,3-diaza'indol-4-ylamino}-. -yl)· Piperazine-1-decanoic acid ethyl ester, 0 丫Ν) Ο 1-87 8-Fluoro-6-(2-fluoro-1,1-dimercapto-ethyl)-2-(2- Hydroxymercapto-3-{1-methyl-5·[5-(N-line-4-benzylidene-2-ylamino)-6-sideoxy-1,6-diaza-violet -3-yl}-phenyl)-2//-isoquinoline ketone. 丫 人 人 irVNJ 〇人1 1-88 6-t-butyl-8-fluoro-2-(2-hydroxyindoleyl) -3-{1-methyl-5-[5-((lS,4S)-5-mercapto-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-&quot; Indole-2-ylamino]-6-sideoxy-1,6.diaza-vioran-3-yl}phenyl)-2//-°Tetazine-1-S is the same as Υτ^ O^ N. HO hn^^yVn'n^ $ 1-89 2-[8-fluoro-2-(2-pyridyl-3-{didecyl-5-[5-((R)-l-fluorenyl)- Pt ρ each bite 3-yl)-.咬-2-ylamino]-6-o-oxy-1,6-diaza-contain 17-methyl-3-yl}-phenyl)-1-oxo-1,2-diaza-iso喧-6-yl]-2-mercapto-propionitrile 0γΝ'ρ}ϊ0^ °Vy σ υ ύ,

157475.doc ·66· 201211039 -------- 6-Tertibutyl-8-fluoro·2-(2_hydroxyformamidine----- X Ν XI Ϊ -3- -3- _ 1 1 -mercapto-6-sideoxy_5· [Γ-(2,2,2-trifluoro-ethyl)-ho^ 1-90 1',2|,3',4',5',6 |-hexa-argon-[3,4|]-linked to nh 4 pyridin-6-ylamino]-1,6-dihydro-pyridazine small group}-phenyl)-2 pressure 呔口秦-1-_ F FF r - synthetic general synthetic process

This application is related to the U.S. Patent Application Serial No. 12/711,312, filed on Feb. 24, 201, the disclosure of which is hereby incorporated by reference in its entirety.

Mel, DMF Cs2C03

Intermediate A h2so4 H2N^N Η0Α:

Br Everyone Cl »2〇 Commercially available CAS:446273-59-2

Pd(dba) process Π Xphos

Wherein Y4 may be Y4a, Y4b, Y4e or Y4d; Y4a may be a halogen; y4b may be a lower alkyl group as the case may be selected from one or more selected from the group consisting of lower haloalkyl, halogen, hydroxy, amine, cyano And the substituent of the group of lower alkoxy groups is taken as 157475.doc -67-201211039 generation; Y4e may be a lower alkylcycloalkyl group, optionally selected from lower alkyl, lower haloalkyl groups by one or more a substituent of a group consisting of a halogen, a hydroxyl group, an amine group, a cyano group, and a lower alkoxy group; and Y4d may be an amine group, optionally having one or more lower alkyl groups, alkoxy lower alkyl groups Or a hydroxy lower alkyl group.

Process III

R-CI

2-(dicyclohexylphosphino)biphenyl

BMS HC1 Xantphos Cs2C03

R-nh2

Acetone) dipalladium (0)

Diphenyl sulfhydryl

CI ginseng (diphenylarylene acetonide) dipalladium (0) bis(trimethyl fluorenylalkyl) aminated lithium

Xantphos Tripotassium Phosphate (Diphenylarylene) Acetone Palladium (0)

Wherein R can be Η, -R1, -Ri-R^-R3, -Ri-R3 or -R2-R3; R1 can be aryl, heteroaryl, bicycloheteroaryl, cycloalkyl or heterocycloalkyl Each may optionally be subjected to one or more lower alkyl, hydroxy, hydroxy lower alkyl, lower alkoxy, halo, fluorenyl, amine, acid amine, cyano, pendant or lower Carbohaloalkyl substituted; R2 can be -C(=0), -C(=0)0, -C(=0)NR2', -NHC(=0)0, -C(R2')2, - Ο, -S, -C(=NH)NR2' or -S(=0)2; 157475.doc •68- 201211039 Each R2 may independently be a hydrazine or a lower alkyl group; R3 may be H*R4; R4 It can be low-stone anthracyl, low-carbon-burning, low-carbon alkoxy, amine, low-carboalkylamine, cycloalkylamine, low-carbon amphoteric amine, aryl, aryl Alkyl, alkylaryl, heteroaryl, alkylheteroaryl, heteroarylalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, heterocycloalkyl, arylcycloalkylene , heterocycloalkylalkyl, bicyclocycloalkyl, bicycloheterocycloalkyl, spirocycloalkyl, spiroheterocycloalkyl or bicyclospirocycloalkylene, each optionally having one or more lower alkyl groups , functional group, lower alkylamine Base, lower carbon dialkylamino group, hydroxyl group, hydroxy lower alkyl group, lower alkoxy group, lower alkyl alkano group, picture group, nitro group, amine group, decylamino group, fluorenyl group, cyano group, side Oxyl, sulfonyl, lower alkylsulfonyl, fluorenyl, hydroxyamino, carboxy, aminemethanyl, urethane, valyl alkoxy, heterocycloalkyl or dentate Lower alkyl substituted wherein two lower carbon groups can form a ring together.

157475.doc 69· 201211039

NH

R flow ιν

Acetone) dipalladium (0)

Intermediate D

Wherein R can be -R2-R3 or -R3; R2 can be -C(=0), -C(=0)0, -C(=0)NR2', -NHC(=0)0, -C( R2')2, -O, -S, -C(=NH)NR2' or -S(=0)2; each R2' may independently be H or lower alkyl; R3 may be H or R4; R4 It may be a lower alkyl group, a lower carbon dentate group, a lower alkoxy group, an amine group, a lower alkylamino group, a cycloalkylamino group, a lower carbodialkylamino group, an aryl group or an arylalkyl group. , alkylaryl, heteroaryl, alkylheteroaryl, heteroarylalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, heterocycloalkyl, alkylheterocycloalkyl, Heterocycloalkylalkyl, bicyclic cycloalkyl, bicycloheterocycloalkyl, spirocycloalkyl, spiroheterocycloalkyl or bicyclospirocycloalkyl, each optionally having one or more lower alkyl groups, Toothyl, lower alkylamino, lower dialkylamino, hydroxy, hydroxy lower fluoro, lower alkoxy, lower carbyl, ii, fluorenyl, amine 157475.doc •70 - 201211039, amidino, fluorenyl, cyano, pendant oxy, sulfonyl, lower alkyl sulfonyl, fluorenyl, hydroxyamino, carboxy, amine carbyl, urethane Halogen-based low carbon Alkoxy, heterocycloalkyl or dentate lower alkyl substituted wherein two low carbon building groups may together form a ring.

Lithium bis(trimethyldecyl) amination

Ginseng (diphenylmethyleneacetone) dipalladium (9)

Xantphos Cs2C03

Reference (diphenylarylene) acetone dipalladium (9) α gin (diphenylarsinone) dipalladium (9)

Wherein each R 2 ' may independently be hydrazine or lower alkyl; Υ 4 may be Y 4a, Y 4b, y 4c or Y 4d ; Y 4a may be hydrazine or halogen; Y 4b may be lower alkyl, optionally selected from one or more Substituted by a substituent of a group consisting of a low carbon-alkyl group, a halogen, a hydroxyl group, an amine oxime, a cyano group and a lower alkoxy group; Y4c may be a lower carboalkyl group, optionally selected from a lower alkane by one or more Substituted by a group consisting of a group of lower, lower haloalkyl, _, hydroxy, amine, cyano and lower alkoxy; 157475.doc -71 - 201211039 and 丫4£1 may be an amine group, The situation is replaced by one or more lower alkyl, alkoxy lower aryl or trans-base low carbon alkyl groups.

Process VI

RrMgI HOAc Na2C03

2-(dicyclohexylphosphino)biphenyl

MeCN HOAc H2S04 NaOH °γΝ'Ν Br^^Cl

BMS Xantphos Cs2C03 ginseng (diphenylmethyleneacetone) dipalladium (c〇 HC1

Phenol (diphenylarylene) acetone dipalladium (0) bis(trimethyldecyl) aminated lithium

Or Y, Y4a may be hydrazine or halogen; Y4b may be a low carbon alkyl group, optionally consisting of one or more selected from the group consisting of a lower halogen haloalkyl group, a hydroxy group, a hydroxyl group, an amine group, a cyano group and a lower alkoxy group. Substituted by a group of substituents; γ4. It may be a lower carboalkyl group, optionally substituted by one or more groups selected from the group consisting of lower alkyl, lower alkyl, dentate, thiol, amino-cyano and lower alkoxy Substituent; and Y may be an amine group, optionally substituted with one or more lower alkyl, alkoxy lower alkyl or via a lower alkoxy group. The pyridazinone derivatives described herein are kinase inhibitors, particularly Btk inhibitors 157475.doc • 72·201211039 agents. These inhibitors can be used to treat one or more diseases in response to kinase inhibition in mammals, including Btk Inhibition and/or inhibition of 8-cell proliferation inhibits the disease. Without wishing to be bound by any particular theory, it is believed that the interaction of a compound of the invention with Btk inhibits Btk activity and thereby produces the pharmaceutical utility of such compounds. Accordingly, the present invention includes a method of treating a mammal (e.g., a human) having a disease responsive to inhibition of Btk activity and/or inhibition of B cell proliferation, comprising administering at least a mammal having such a disease an effective sputum A chemical entity provided herein. The effective concentration can be determined experimentally, for example, by assaying the blood concentration of the compound, or by rationally, by calculating the bioavailability. Other kinases that may be affected in addition to Btk include, but are not limited to, other tyrosine kinases and serine/threonine kinases. Kinases play a significant role in controlling the signaling pathways of essential cellular processes such as proliferation, differentiation and death (apoptosis). Abnormal kinase activity has been implicated in a wide range of diseases including a variety of cancers, autoimmune diseases and/or inflammatory diseases, and acute inflammatory responses. The multifaceted role of kinases in key cell signaling pathways provides a significant opportunity to identify novel drugs that target kinases and signaling pathways. One embodiment includes a method of treating a subject having an autoimmune disease and/or an inflammatory disease or an acute inflammatory response that is responsive to inhibition of Btk activity and/or sputum cell proliferation. Autoimmune diseases and/or inflammatory diseases that may be affected by the use of the compounds and compositions of the invention include, but are not limited to, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, Hughes Disease 157475.doc -73- 201211039 (Sjogren's disease), tissue transplant rejection and hyperacute rejection of transplanted organs, asthma, systemic lupus erythematosus (and related spheroid nephritis), dermatomyositis, multiple sclerosis, hard Skin disease, vasculitis (ANCA-associated vasculitis and other vasculitis), autoimmune hemolytic and thrombocytopenic conditions, Goodpasture's syndrome (and related spheroid nephritis and pulmonary hemorrhage), atherosclerosis Hardening, rheumatoid arthritis, chronic idiopathic thrombocytopenic purpura (ιΤΡ), Addison, s disease, parkinson's disease, Alzheimer's disease ), diabetes, septic shock and myasthenia gravis. The invention includes a method of treatment in which at least one of the chemical entities provided herein is administered in combination with an anti-inflammatory agent. Anti-inflammatory agents include, but are not limited to, NS AID, non-specific and COX-2 specific epoxidase inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors Antagonists, immunosuppressive agents and amidoxime. Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen, naproxen sodium, diclofenac, Combination of diclofenac sodium with misoprostol, sulindac, oxaprozin, diflunisal. Piroxicam, 0 bow 丨 0 mexin (indomethacin), etodolac (et〇d〇lac), fenoprofen calcium, ketoprofen, nabendene Sodium nabumetone, suifasaiazine, tomi 157475.doc •74- 201211039 Tolmetin sodium and hydroxyquinoquine hydrazine xychl〇r〇quine 〇NSAID examples also include COX -2 specific inhibitors, such as celecoxib, vaidecoxib, lumiracoxib and/or et〇ric〇xib. In some embodiments, the anti-inflammatory agent is a salicylate. Salicylic acid salts include, but are not limited to, acetaminophen or aspirin, sodium salicylate, salicylic acid, and salicylic acid. 4 inflammatory agents can also be corticosteroids. For example, corticosteroids can be cortisone, dexamethas〇ne, methylprednisolone, prednis〇i〇ne, prednisolone sodium. Phosphate) or precinisone. In other embodiments, the anti-inflammatory agent is a gold compound such as gold sodium thiomalate or auranofin. The invention also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor such as a diargonylate reductase inhibitor such as methotrexate; or a dihydro whey φ acid dehydrogenase inhibitor such as leflunomide ( Leflimomide). Other embodiments of the invention pertain to combinations wherein at least one anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab); a TNF antagonist such as ena EnanterCept or infliximab, an anti-TNFa monoclonal antibody. Other embodiments of the invention relate to combinations wherein at least one active agent is an immunosuppressant compound, such as selected from the group consisting of methotrexate and leflunomide. l cyclosporine, tacr〇iimus, thiosulfate 157475.doc •75- 201211039 za (azathioprine) and mycophenolate mofetil immunosuppressive compounds. B cells and B cell precursors that express BTK have been implicated in the pathology of b cell malignancies. These B cell malignancies include, but are not limited to, B cell lymphomas, lymphomas (including Hodgkin's lymphoma ( Hodgkin's lymphoma and non-Hodgkin's lymphoma (s), hairy cell lymphoma, multiple myeloma, chronic and acute osteomyelitis, and chronic and acute lymphocytic leukemia. BTK has not been shown to be an inhibitor of the signaling complex (DISC) that induces Fas/APO-1 (CD-95) death in lymphoid cells. The fate of leukemia/lymphoma cells may lie in the balance between the late-promoting effect of the caspase-activated cell by DISC and the upstream anti-apoptotic regulatory mechanisms involved in BTK and/or its receptor (Vassilev et al. J.仏0/· c/zem. 1998, 274, 1646-1656). It has also been found that BTK inhibitors are useful as chemosensitizers and are therefore useful in combination with other chemotherapeutic agents, particularly those that induce apoptosis. Examples of other chemotherapeutic agents that can be used in combination with chemosensitizing BTK inhibitors include topoisomerase I inhibitors (camptothecin or topotecan), topoisomerase π inhibitors (eg daunomycin and et〇p〇side), alkylating agents (eg cyclophosphamide, melphalan and BCNU), tubulin-directed Agents (eg, taxol 1 and vinblastine), and biological agents (eg, antibodies such as anti-CD2 antibody, IDEC 8, immunotoxins, and cytokines). 157475.doc 201211039

Btk activity has also been associated with a number of leukemias that exhibit fusion genes produced by partial translocations of chromosomes 9 and 22. This abnormality is usually observed in chronic medullary leukemia. The Btk line is constitutively filled with a kinase which initiates the downstream survival of the cell which prevents apoptosis of cells (N. Feldhahn et al., 乂 叩 从 from 2005 201(11): 1837-1852). The compounds of the present invention can be formulated into a variety of oral administration forms with carriers. Oral administration can be in the form of a troche, a coated lozenge, a dragee, a hard and soft gelatin capsule, a solution, an emulsion, a syrup or a suspension. The compounds of the invention are effective when administered by other routes of administration, and other routes of administration include continuous (intravenous infusion) topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include penetration enhancers) , frequency, nasal, inhalation and suppository administration. The preferred mode of administration is generally oral administration using a suitable daily dosing regimen which can be adjusted depending on the degree of the disease and the patient's response to the active ingredient. The compounds of the present invention, as well as the pharmaceutically acceptable salts thereof, may be formulated into a pharmaceutical composition and unit dosage form together with one or more of the known excipients, carriers or diluents. The pharmaceutical compositions and unit dosage forms may contain conventional ingredients in the ordinary proportions, with or without other active compounds or components, and the unit dosage form may contain any suitable effective amount that is compatible with the intended dosage range to be used. The active ingredient H composition can be used in the form of a solid such as a lozenge or a filled capsule; a semisolid; a powder, a continuous formulation; or a liquid such as a solution, suspension, emulsion, granule or capsule for oral use. Or an enteric agent for rectal or vaginal administration; or a sterile injectable solution for parenteral use. A typical preparation will contain from about 5% to about 157475.doc -77 to 201211039 about 95% active compound (w/w). The term "formulation" or "dosage form" is intended to include both solid and liquid formulations of the active compound, and those skilled in the art will appreciate that depending on the dry organ or tissue and the desired dosage and pharmacokinetic parameters, the active ingredient may be Different forms of preparation exist. The term "excipient" as used herein refers to a compound that is suitable for the preparation of a pharmaceutical composition, which is generally safe, non-toxic, and biologically and otherwise desirable, and includes both livestock and humans. Excipients accepted for medical use. The compounds of the invention may be administered separately, but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected for the intended (4) route and standard (iv) specifications. "Pills can be taken on" means that it is suitable for the preparation of pharmaceutical compositions which are generally safe, non-cracking and biologically and otherwise desirable and which are acceptable for use in livestock and human medicine. . The "pharmaceutically acceptable salt" form of the active ingredient may also initially impart the desired pharmacokinetic properties of the active ingredient which are not possessed by the non-salt form and may even affect the therapeutic activity of the active ingredient in vivo. Pharmacodynamics. "Pharmaceutically acceptable salt" of a phrase compound means a salt which is pharmaceutically acceptable and which has the desired pharmacological activity of the parent compound. Such sleeps include: (1) acid addition salts with inorganic acids such as capric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or acid additions formed with organic = Salt, such organic acids are such as acetic acid, propionic acid, acid 7 cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, _5L, succinic acid, malic acid, maleic acid, anti Butenedioic acid, tartaric acid, citric acid, benzene f acid, 3-(4-hydroxybenzyl)benzoic acid, cinnamic acid, mandelic acid, A 157475.doc -78 - 201211039

Alkanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethane acid, benzenesulfonic acid, 4-gasbenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid , camphor acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 3-phenylpropionic acid, tridecyl acetic acid, tert-butylacetic acid, laurel Sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) when the acidic protons present in the parent compound are, for example, metal ions, a salt formed by replacement of an alkaline earth metal ion or a metal ion of an aluminum ion, or an acidic proton present in the parent compound such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and a salt formed when the organic base of the analog is coordinated. Solid form preparations include powders, troches, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, (d) disintegrants or encapsulating materials. In powders, the carrier is typically a finely divided solid in admixture with the finely divided active component. In lozenges, the active component will generally be mixed in a suitable ratio with the carrier having the necessary adhesive strength and compressed into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth: methylcellulose, sodium carboxymethylcellulose, low Melting point wax, cocoa butter: an analogue thereof. The solid form preparation may contain, in addition to the active ingredient, a flavor, a stabilizer, a buffer, an artificial and natural sweetener, a diluent, a thickener, a hydrazine solvent, and the like. Liquid formulations are also suitable for oral administration, and liquid formulations include emulsions, aqueous solutions, aqueous suspensions. Such formulations include the solid form 劁 u ® which is intended to be converted to a liquid form preparation prior to use 157475.doc • 79-201211039. The boring solution can be prepared in a solution (e.g., in an aqueous solution of propylene glycol), or an emulsifier such as lecithin, leucovorin monooleate or gum arabic. The aqueous solution can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents. The aqueous suspension can be prepared by dispersing the finely divided active ingredient in a water-retaining material with a viscous material such as natural or synthetic gum, resin, methylcellulose, sodium methylcellulose, and other well-known materials. The compounds of the invention may be formulated for parenteral administration (for example by injection, such as bolus injection or continuous infusion), and may be presented in unit dosage form in ampoules, prefilled syringes, in small volume infusion containers or with added antiseptic The agents are present together in a multi-dose container. The composition may take the form of a suspension, solution or emulsion such as in an oily or aqueous vehicle such as a solution in aqueous polyethylene glycol. Examples of oily or non-aqueous vehicles, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate), and may contain, for example, preservatives, A formulation of wetting agents, emulsifiers or suspending agents, stabilizers and/or dispersing agents. Alternatively, the active ingredient may be in the form of a powder which is obtained by the sterile separation of the sterile solids or by the solution from the solution of the lyophilic solution for reconstitution with a suitable vehicle (for example, sterile, pyrogen-free water) before use. . The compounds of the invention may be formulated as ointments in the form of a cream or lotion or in the form of a transdermal patch for topical administration to the epidermis. Ointments and creams may be formulated with aqueous or oily matrices, for example, with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with aqueous or oily matrices and will generally contain one or more emulsifying, stabilizing, dispersing, suspending, thickening or coloring agents. 157475.doc • 80 · 201211039 Formulations for topical administration of sputum include ingots, which are included in the flavoring base (usually sucrose and gum arabic or tragacanth), tablets, It is contained in an inert matrix (such as gelatin and glycerin or sucrose and gum arabic) "active ingredient; and an expectorant, which is included in a suitable liquid carrier. / ,

The compounds of the invention may be formulated for suppository administration for administration. First, the mixture of the fatty acid glycerides of the sulphuric acid or the low melting point wax of cocoa butter is melted, and the active component is uniformly dispersed, for example, by stirring. The molten homogeneous mixture is then poured into a mold of suitable size, allowed to cool and solidify. σ The compounds of the invention may be formulated for vaginal administration. A pessary, tampons, cream, gelatinous paste, foaming agent or spray containing a carrier known in the art in addition to the active ingredient is suitable. The compounds of the invention may be formulated for nasal administration. By way of conventional means, for example, the (iv) tube m spray (tetra) float is applied directly to the nasal cavity. The formulation τ is presented in a single dose or in multiple doses. In the case of a dropper or a pipette, this can be achieved by administering a suitable predetermined volume of solution or suspension to the patient under conditions of the nebulizer, which can be achieved, for example, by means of a metered atomizing jet pump. The compounds of the invention may be formulated for administration to an aerosol, especially to the respiratory tract and include sputum. The compound will generally have a small particle size of, for example, about 5 microns or less. Such particle size can be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized packaging towel having a suitable propellant. The propellant is, for example, a gas-gas carbide (CFC) (for example, dichlorodifluoromethane, tri-fluoro or tri-fluorotetrafluoroethane) or carbon dioxide. Or its 157475.doc •81 · 201211039 He is suitable for gas. Aerosols should also contain a surfactant such as an egg fat. The drug dose can be controlled by a metering valve. Alternatively, the active ingredient may be presented in the form of a powder, such as a compound in a powder base such as lactose, starch, starch derivatives (such as hydroxypropyl decyl cellulose) and polyvinylpyrrolidone (in the form of a powder mixture suitable for use in a powder base) PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dosage form in a capsule or cartridge, e.g., gelatin or blister pack, from which the powder may be administered by means of an inhaler. If desired, the formulation can be prepared as an enteric coating having a sustained or controlled release administration suitable for the active ingredient. For example, the compounds of the invention may be formulated in a transdermal or subcutaneous drug delivery device. Such delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with the treatment regimen is critical. Compounds in transdermal delivery systems are often attached to skin-adhesive solid structures. The relevant compound can also be combined with a penetration enhancer such as Azone (l-dodecanyl aza-cycloheptan-2-one). The sustained release delivery system is inserted subcutaneously into the subcutaneous layer by surgery or injection. The subcutaneous implant encapsulates the compound in a lipid soluble membrane (e.g., polyoxyxene rubber) or a biodegradable polymer (e.g., polylactic acid). Suitable formulations as well as pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Skilled blending scientists can modify the formulation to provide a multitude of formulations for a particular route of administration without the teachings of the present invention being unstable or impairing the therapeutic activity. 157475.doc -82- 201211039 ^The compounds of the invention are modified to make them more chillable in water or other vehicles, for example by minor modifications (salt formulation, brewing, etc.) that are well within the skill of the general practitioner. ) to be easy to implement. Modification of the route of administration of a particular compound and dosing regimen a manages the pharmacokinetics of the compounds of the invention to achieve maximum beneficial effects in the patient, which is well within the skill of the ordinary artisan. The term "therapeutically effective amount" as used herein means the amount required to alleviate the symptoms of an individual's disease. In each specific situation, the agent will be adjusted according to individual needs. The dose can vary within a wide range, depending on a number of factors, such as the severity of the disease, the age and general health of the patient, the other agents used to treat the patient, the route and form of administration, and the preferences of the relevant practitioner. And experience. For oral administration, a daily dose of between 001 mg and about 1 mg per kg of body weight per day should be appropriate in monotherapy and/or combination therapy. Preferably, the dose is about (U mg) of about 500 mg per kilogram of body weight per day, more preferably between ο mg and about gram per kilogram of body weight per day, and optimally 1 gram per kilogram of body weight per kilogram. Between about 1 mg and mg. Therefore, for 70 (four) solids, the dose should range from about 7 mg to 0.7 g per day. The daily dose can be administered in a single dose or in divided doses. Between 5 and 5 doses. In general, treatment is initiated with a smaller dose that is less than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the individual patient achieves optimal results. The general practitioner should be able to determine the therapeutically effective amount of the compound of the present invention against a given disease and patient without undue experimentation and relying on personal knowledge, experience, and disclosure of the present application. 157475-doc -83- 201211039 Pharmaceutical The preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be packaged, for example, as a packaged lozenge, capsule, and bottled or ampoules. The package contains an individual amount of the formulation. Also, the unit dosage form can be a capsule, lozenge, cachet or troche itself, or it can be any one of these unit dosage forms in a suitable package. [Examples] Examples of commonly used abbreviations include: acetonitrile (Ac), azobisisobutyronitrile (AIBN), atmospheric pressure (Atm), 9-boronbicyclo[3.3.1] decane (9-BBN or BBN) , 2,2'-bis(diphenylphosphinobinaphthalene (BINAP), tert-butoxycarbonyl (Boc), di-tert-butyl dicarbonate or boc anhydride (B0C20), benzoinyl (Bn), Butyl (Bu), CAS No. CASRN, benzoxyloxycarbonyl (CBZ or Z), carbonyldiimidazole (CDI), 1,4-diazabicyclo[2.2.2]octane (0 Eight 8 (:0), diethylaminosulfur trifluoride (0,81,8,diphenylhydrazinylacetone (dba), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N'-dicyclohexylcarbodiimide (DCC), 1,2-digas Ethane (DCE), dihydromethane (DCM), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), diethyl azodicarboxylate DEAD), diisopropyl azodicarboxylate (DIAD), diisobutylaluminum hydride (DIBAL or DIBAL-H), diisopropylethylamine (DIPEA), N,N-dimercaptoacetamide (DMA), 4-anthracene, fluorenyl-didecylaminopyridine (DMAP), hydrazine, hydrazine-dimethylformamide (DMF), diterpenoid (DMS0), 1, bismuth-bis(diphenyl) Ethylphosphine) ethane (dppe), 1,1'-bis(diphenylphosphino)diphenyl 157475.doc -84- 201211039 iron (dppf) ' 1-(3-dimethylaminopropyl) _3_Ethylcarbodiimide hydrochloride (EDCI) '2-Ethoxy-1-ethoxycarbonyl-indole, dihydroindan (EEDQ), ethyl (Et), ethyl acetate (EtOAc) , Ethanol (Et〇H), 2 Ethoxy-2β-quinoline-1-carboxylic acid ethyl ester (EEdQ), diethyl ether (as 2 〇), ethyl isopropyl ether (EtOiPr) 六 hexafluorophosphate 〇 ( 7_azabenzotriazole·yl)_N,N,N'N'-tetramethylguanidine (HATU), acetic acid (HOAc), 1_Ν·hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), isopropanol (ΙΡΑ), isopropylmagnesium chloride (iPrMgCl), hexamethylene diazoxide (HMDS), hexane (hex) liquid chromatography mass spectrometry (LCMS), Rokko Base two Indole azide (LiHMDS) 'm-gas peroxybenzoic acid (m-CPB A), methanol (MeOH), refining point (mp), MeS02-(sulfonyl sulfhydryl or Ms), mercapto (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPB A), mass spectrometry (ms), methyl tert-butyl ether (MTBE) 'mercaptotetrafuran (MeTHF), N-bromosuccinimide (NBS ), n-butyllithium (nBuLi), N-carboxy anhydride (NCA), N-gas succinimide (NCS) 'N-methylmorpholine (NMM), N-methylpyrrolidone (NMP) ) 'Chromium chromite barium ingot (PCC), dichloro-((bisdiphenylphosphino)ferrocenyl)palladium(II) (Pd(dppf)Cl2), palladium(II) acetate (Pd(OAc)) 2), ginseng (diphenylmethyleneacetone) dipalladium (p) (Pd2 (dba) 3), dichromic acid. Specific ingot (PDC), phenyl (Ph) 'propyl (pr), isopropyl (z__pr), broken / square 忖 (pSi), „比定(卩丫〇'1,2,3,4, 5-pentaphenyl-1'-(di-t-butylphosphino)ferrocene ((5_ Phos) 'room temperature (ambient temperature, "or rT), second butyl lithium (sBuLi), third butyl Dimethyl decyl or i-BuMe2Si (TBDMS), tetra-n-butylammonium fluoride (TBAF), triethylamine (TEA or Et3N), 2,2,6,6-tetramethylpiperidine 1-oxygen TEMPO, triflate or CF3S02-(Tf), trifluoroacetate 157475.doc •85· 201211039 (TFA), 1, Γ-bis-2,2,6,6-tetradecyl Geng-2,6-dione (TMHD), bismuth tetrafluoroborate-benzotriazol-1-yl-indole, hydrazine, Ν', Ν'-tetramethyl hydrazine (TBTU), thin layer chromatography TLC), tetrahydrofuran (THF), trimethylsulfonyl or Me3Si (TMS), mono-p-toluenesulfonic acid (TsOH or pTsOH), 4-Me-C6H4S02- or acesulfonyl (Ts), and N -Amino phthalate-N-carboxy anhydride (UNCA). It includes the knowledge of prefix ("), iso (/-), second 〇%-), third (kri-) and neo (neo). Naming has its usual meaning when used with an alkyl moiety (J. Rigaudy D. P. Klesney, TV'owewc / aiwre k IUPAC 1979 Pergamon Press, Oxford.). 1-1 Preparation of

Step 1. Preparation of 2-(6-apyridin-3-yl)propan-2-ol 157475.doc • 86 · 201211039

I 1

〇Cl plant OH A solution of 6-gas nicotine helium (38.037 g, 216 mmol, 1.00 equiv) in dry diethyl ether (200 ml) was added dropwise to a stirred solution of methyl iodide at room temperature. Magnesium solution (158 ml, 475 mmol, 2.2 eq.). After the addition, the reaction mixture was refluxed for 3 hours. The reaction was quenched by pouring the mixture into stirring ice/200 ml of acetic acid mixture, sodium bicarbonate was added until pH 8 and extracted with diethyl ether. The sodium was dried and concentrated to give a yellow solid (30.15 g, 0.175 mol). MS (Η+)=172·1 Step 2. Preparation of Ν-(2-(6-chloropyridin-3-yl)propan-2-yl)acetamide

2 (6-Chloropyridin-3-yl)propan-2-ol (637 mg, 3.71 mmol, l.oo was dissolved in acetonitrile (5 ml). Acetic acid (2.9 g, 2.76^, 48·3 mmo1 , 13 equivalents), and after cooling, cooled to 〇t. Concentrated sulfur &amp; (5·1 g '2·77 nU' 52.0 mm〇i, 14 equivalents) was added dropwise to the solution' The mixture was poured into ice overnight. The reaction mixture was poured into ice. 'The concentrated NaOH solution was added until it was tested. The organic phase was extracted with brine. The organic phase was washed with brine and dried over sodium sulfate to give a yellow solid 157475. .doc -87- 201211039. Acetate and a small amount of chilled residue. Obtain the resulting precipitate to give a white solid (ns mg, i 59 mm 〇l). MS (H+) = 213.i Step 3. Preparation of 2-(6-chloropyridine-3-yl)_N_ethylpropan-2-amine

ό C, X and Η Dissolve Ν ° ) ) ) ) 丙 基 基 基 基 ( ( ( ( ( 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 BMS (2 Μ in THF) (53 ml, 1 〇 6 〇 〇 1, 2 eq.) was added dropwise to /dissolved and refluxed overnight. The concentrated HCl solution 5 (7) was slowly added to the refluxing reaction mixture to make up for 1 hour. The reaction mixture was concentrated in vacuo. The crude material was dissolved in a two-flux M fertilizer solution towel. The aqueous phase was collected and treated with a saturated aqueous solution of sodium carbonate. The crude product was purified by silica gel chromatography to give a yellow gum (8. 〇3g '40.4 </ br> </ br> </ br> used as the next step. Step 4. Preparation of 5-(1-ethylaminomethyl) _Ethyl)_pyridine_2_ylamine

I57475.doc • 88 - 201211039 2-(6-Chloro 0-but-3-yl)-N-ethylpropan-2-amine (5 g '25·2 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (13 0 ml) Shen. 2-(Dicyclohexylphosphino)biphenyl (1.76 g, 5.03 mmol, 〇. 2 eq.) and gins (diphenylmethylene acetonate) two (0) (2.3 g) were added sequentially under an argon atmosphere. 2.52 mmol, 0.1 eq.). Finally, THF (75.5 m, 75.5 mmo, 3 equivalents) containing 1 bis bis(tridecyldecylalkyl) amination was added dropwise. The reaction mixture was stirred overnight at 90 ° C in a sealed flask. The reaction mixture was poured into aq. EtOAc (EtOAc) The crude material was purified by flash chromatography eluting elut elut elut elut elut elut 4 NMR (300 MHz, chloroform δ ppm 1.06 (t, "7=1.00 Hz, 3 Η) 1.44 (s, 6 H) 1.86 (s, 1 H) 2.37 (q, J=1.00 Hz, 2 H) 4.39 ( s, 2 H) 6.49 (d, J=l.〇〇Hz, 1 H) 7.55 (d, J=l.〇〇Hz, 1 H) 8.08 (s, 1 H) Step 5. Preparation 6_Air B Amino-1-yl-ethyl-ethyl)-pyridin-2-ylamino]-2-mercapto-2H-pyridazine-3-one

This reaction is carried out under conditions similar to those described in Step 6 of Preparation. 157475.doc -89· 201211039 After treatment, the product was purified by silica gel preparative HPLC using a gradient of 2% to 8% methanol / dioxane. This gave the desired product (328 mg) as a yellow powder. (M+H)+=322 m/e.

Pd(dba)

Xphos κ3ι&gt;ο4 To the microwave reaction flask was added 2-(6-t-butyl-8-fluoro-1-oxo-1H-pyridazin-2-yl)-6-chloro-phenylmethyl acetate (329). Mg, 0.818 mmol), bis(pinacolyl) II (416 mg, 1.637 mmol), KOAc (241 mg, 2.454 mmol) and Xphos (39 mg, 0.0818 mmol) and II. In a bad burn (4 mL). Argon was bubbled through for 15 minutes&apos; followed by the addition of Pd(dba)2 (24 mg, 0.0409 mmol). The tube was sealed and heated to 60 ° C for 18 hours. The reaction mixture was diluted with EtOAc (5 mL)EtOAcEtOAcEtOAc. The org. -2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaboran-2-yl)-benzamide (33 0 mg, 81%) . Step 6. Preparation of 2-(6-t-butyl-8-fluoro-1-oxo-1H-pyridazin-2-yl)-6-{5-[5-(1-ethylamino)acetate -didecyl-ethyl)-pyridin-2-ylamino]-1-indolyl-6-o-oxy-1,6-dihydro-pyridazin-3-yl}-phenylmethyl ester 157475.doc •90· 201211039

This reaction was carried out under the conditions similar to the step 7 of the preparation of K. After the treatment, the product was purified by preparative TLc (3 disks) by elution with 10 〇 / 〇 methanol / dichloromethane. This gave the desired product as an orange-yellow foam (as well as some of the de-branched product) (3 〇 3 mg). (M+H)+=654 (612) m/e. Example 1 Step 7. Preparation of 6-t-butyl-2-(3-{5-[5-(1-ethylamino-1-methyl-ethyl)-pyridin-2-ylamino]- 1-methyl_6_sideoxy-丨,6-dihydro-pyridazine_3_yl}_2-hydroxymethyl-phenyl)-8-fluoro-2H-pyridazin-1-one

This reaction was carried out under the conditions similar to the procedure of Step 8 of Preparation 1-6. After the treatment, the preparation was carried out by using 2% to 10% decyl alcohol*/dichloromethane (*methanol containing 2% ammonium hydroxide). To purify the product. The product was collected and further purified by autothermal isopropyl acetate/hexane. The crystalline product was collected by 157475.doc.91.201211039 to give the desired product (341 mg) as a pale yellow-white powder. MP = 229-233 ° C. (M+H)+=612 m/e. Page 079. 1Η NMR (3 00 MHz, gas pattern _d) § ppm 1,05 (t, /=7.18 Hz, 3 Η) 1.32-1.59 (m, 15 Η) 2.38 (q, 7=7.20 Hz, 2 H) 3.81 -4.05 (m, 4 H) 4.43 (s, 2 H) 6.93 (d, J=8.31 Hz, 1 H) 7.39-7.82 (m, 6 H) 8.28 (d, J=2.64 Hz, 2 H) 8.40 ( d} J=2.27 Hz, 1 H) 8.64 (s, 1 H) 〇Preparation 1-2

6-Gas-2-methyl-4-[5-(morpholin-4-carbonyl)-pyridin-2-ylamino]-2H-pyridazin-3-one 6-Aminopyridin-3-yl -(N-morpholinyl)-methanone (800 mg, 3.86 mmol, 1.00 equiv), 4-bromo-6- ox-2-mercaptopyridin-3(2H)-one (1 g, 4.48 mmol, 1.16 equivalents, carbonic acid (4.4 g, 13.5 mmol, 3.5 equivalents) and xantphos (33 5 mg, 579 μηηοΐ, 〇. 15 equivalents) were suspended in dioxane (40 ml). The suspension was degassed with argon. Finally, Pd2(dba)3 (265 mg, 290 μιηοο 0.075 equivalent) was added at 90. (The reaction mixture was stirred overnight under argon atmosphere. The reaction mixture was cooled to room temperature then filtered over Celite. The filtrate was concentrated in vacuo to give a pale brown 157 s s s s s s s s s s s s s s s s s s s s s The crude material was purified (EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjj 4 NMR (300 MHz, gas _d) δ ppm 3.60-3.80 (m, 8 Η) 3.83 (s, 3 Η) 6.96 (d, /=8.69 Hz, 1 H) 7.77 (dd, J=8.50, 2.45 HZ, 1 h) 8.35-8.44 (m, 2 H) 8.47 (d, /= 2.27 Hz, 1 H). Example 2

6_Ter Butyl-8-fluoro-2-(2-hydroxymethyl-3_U_methyl_5_[5_(morpholine-4-carbonyl)pyrimidin-2-ylamino]-6-sideoxy -1,6-dihydro-anthracene_3_yl}_phenyl)_2H-phthalazin-1-one 6-gas-2-methyl-4-(5-(morpholin-4-carbonyl) Pyridin-2-ylamino)pyridazine_3(2H)-one (200 mg ' 572 μιηοΐ,1 .〇〇 equivalent), acetic acid 2_(6_:butyl -8-fluoro-1-yloxy 0 too 0 Qin-2(1Η)-yl)-6-(4,4,5,5_四曱夷1,3,2 - Oxygen odor-2-yl) This text (525 mg' 743 .μ , 1 3 equivalents) and post-acid hydrazine (652 mg ' 2_00 mmol '3.5 equivalents) were dissolved in 1% by weight of a two-sonic aquaculture solution (3.3 ml). The reaction mixture was heated to i 25 ° C in a microwave to maintain After 35 minutes, the reaction mixture was filtered through celite, and the mixture was extracted with ethyl acetate. The mixture was washed with water and brine. The organic phase was dried over sodium sulfate, and then passed, 157475.doc •93- 201211039 concentrated to give 640 mg The crude material was dissolved in EtOAc (EtOAc) eluted with EtOAc EtOAc EtOAc (EtOAc) l), and add 1 Μ sodium hydroxide solution (858 W, 858 μιηο1, i. 5 eq.) and stir overnight at room temperature. Load the reaction mixture into 24 g column and by flash chromatography (silicone) , 24 g, EtOAc (EtOAc 1:1 EtOAc) EtOAc (EtOAc: EtOAc EtOAc) =215-220°(:,MS (Η+) = 640·1 H NMR (300 MHz, gas § ppm 1 44 (s,9 η) 3 63_3 79 (m, 8 H) 3.93 (s, 3 H ) 4.44 (s, 2 H) 7.05 (d, 1 H) 7.45-7.69 (m, 5 H) 7.75-7.82 (d, 1 H) 8.29 (d, J=2.64 Hz, 1 H) 8.43 (s,1 H) 8.54 (s, 1 H) 8.68 (s, i H). Preparation 1-3

6-Chloro-4-(5-methane hydrazinyl-pyridin-2-ylamino)_2-methyl-2 H-pyridazine-- 4-bromo-6-chloro-2-indenyl 哒3 (2Η)-ketone (1 g, 4.48 mmol, 1.00 eq.), 5-(anthracene) η ratio 0 to 2-amine (771 mg, 4.48 157475.doc -94- 201211039 mmol '1 equivalent) , 4,5-bis(diphenylphosphino)_9,9-didecyldibenzofuran (388 mg, 671 μιηοΐ, 0.15 eq.) and carbonic acid planer (5.1 g, 15 7 mmol, 3.5 畲) Suspended in dioxane (8 〇〇 ml). Finally, ginseng (dibenzylideneacetone) dipalladium (0) (307 mg, 336 μπιο, 0.075 equivalent) was added. The reaction mixture was heated to 90 ° C overnight. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The crude material was wet-purified with dioxane, and the precipitate was collected by filtration to give an off-white solid (70 mg, 222 πηηΐ). 4 NMR (300 ΜΗζ, DMSO-called δ ppm 3.25 (s, 3 Η) 3 69 (s, 3 Η) 7.73 (d, /=8.69 Hz, 1 Η) 8.16 (dd, /=1.00 Hz, 1 η) 8.42 (s,1 Η) 8.83 (d, *7=2.27 Hz, 1 Η) Example 3

6-t-butyl-8-fluoro-2-{2-hydroxymethyl_3·[5_(5_methanesulfonyl-pyridine-2-amino)-1·•methyl-6-side oxygen Benzyl-1,6-dihydro-pyridazine_3_yl]-phenyl}-2H-pyridazine-1-one will be 6-chloro-4-(5-methyl succinct base ratio. Alkyl)_2_methyl_2Η-°ί|oxazin-3-one (40 mg, 127 μιηοΐ, l.oo equivalent), acetic acid 2_(6_t-butyl-8-fluoro-1-yloxy Pyridazine-2(1Η)-yl)_6_(4,4,5,5_tetradecyl_1,3,2- 157475.doc •95· 201211039 oxyboron 0-2-yl) benzoic acid (136 mg, 165 μηιοί, 1.7 equivalents) and carbonic acid (145 mg, 445 μπιοί, 3.5 equivalents) were dissolved in 10% aqueous dioxane (3.3 ml). The reaction mixture was heated to i3 〇〇C in a microwave for 30 minutes. The reaction mixture was filtered through celite. The filtrate was extracted with ethyl acetate and washed sequentially with water and brine. The organic phase was dried over sodium sulfate, filtered and evaporated The crude material was dissolved in ethyl acetate and treated with a broth until a precipitate formed. The precipitate was collected by filtration to give an off-white solid. The solid was dissolved in dioxane (2 mi), and a solution of sodium hydroxide (191 μί, 191 μπιοί, 1.5 eq.) was added and stirred at room temperature overnight. The reaction mixture was loaded into a 12 g column and purified by flash chromatography (矽, 12 §, containing 〇-13%)^6〇11 (it is 1〇8〇1:11^\)) Solid (39 mg, 64·5 μηι〇ι). Mp =225_23〇〇c ,(10) (H+) = 605.3 H NMR (400 MHz, chlorine U) δ ppm ! 36 (s,9 H) 3 〇3 &amp; 3 H) 3.87 (S, 3 H) 4.38 (s , 2 H) 7.00 (d, J=1.00 Hz, 1 H) 7.40-7.61 (m, 5 H) 8.02 (d, ,/=!.〇〇Ηζ, 1 H) 8.22 (s, i H) 8.56 ( Br. s" 1 H) 8.73 (s,1 H) 8.83 (br. s·,1 H). Preparation 1-4 157475.doc -96- 201211039

2-ox-5-(3-decyloxy-azetidinyl-i-ylmethyl.bipyridine: methoxy oxazepine butylate hydrochloride (24.2 g, 198 mmol, 1.00 eq.) Triethylamine (24.0 g, 33.1 ml, 237 mmol '1.2 equivalents) was added to a slurry of 400 mL of di-methane. The precipitate formed was returned to the solution. The subsequent addition of 6-gas nicotine (28 g, 198 mm 〇l, 1.00 eq.) and acetic acid (22.6 ml '3 96 mmol '2.0 eq.). Finally, sodium triethoxy borohydride (41.9 g, 198 mmol, l.oo equivalent) was added portionwise. One ug and wait for a large dispersion. Then add a second U g and check the aliquot by TLc. The residue is still added portion by piece, and the slurry is continuously stirred. After the addition is completed, it is analyzed by TLC. Stirring was continued. After 3 minutes, the reaction appeared to be almost complete. Add 4 mL of water and another 2 mL of a gas to burn, and separate the layers. Use about mL J 〇M Na〇H The aqueous phase was made basic, then extracted three times with 400 mL of dichloromethane, concentrated to give a thick, colorless oil. Vacuum to constant weight 28.3 g (67.3%). · Azetidine-bupyridylpyridine-2-ylamine: 157475.doc -97- 201211039 has 2_gas_5·((3. methoxyazetidin-1- Base) 比 base). Specific bite (11.5 g, 54·1 mmol, 1 ηη 旦, 知·υυ田里), ginseng (diphenylarbenium acetonide) dipalladium (0) (1·24 g mmol, 〇·〇25 equivalents) and biphenyl-2-dicyclohexylphosphine (948 mg, 2'7 mmol, 〇〇5 equivalent) in a round bottom flask with toluene (15 〇ml) added immediately Lithium alkylate alkoxide (8 ι.ι μ, H mmol '1.55 illusion in i 〇M solution in THF. Rapidly refluxed and sorbed overnight under argon. The next day, by τιχ (9: ι McMe〇H) Check the reactants, and sm (starting substance) disappears, mainly replaced by a single lower Rf point. Cool down in sandalwood and add 5 ml of UM HC to mix for 2G minutes and pass through Shixiazao遽°Dilute the filtrate with B. Then wash with 200 mL of 1.0 NaOH NaOH, water and brine. The organic phase was dried over sodium sulfate, filtered and evaporated to give a dark red oil of 14.4 g. Dissolved in CH2C12 and flashed (pure MC 9〇: 1〇

EhN). 4.4 g (42.1%) of the purest dissolving fraction in the form of a reddish oil was collected for use in the next step. 6-Gatro-4-[5·(3-methylindolyl-azetidinyl)-pyridyl-2-ylamino]-2-methyl-2H-pyridazin-3-one : 5_(3_methoxy-azetidinyl)-pyridin-2-ylamine (13〇mg, 0.67 mm〇i, i 〇 equivalent), 4·/odor-6-gas -2-Methyl-2^ 嗓-3--3- 1 (165 mg, 223 mmol, 1.1 eq.), xantphos (58 mg, oi mmol, 〇15 equivalent), ginseng (diphenylmethylene acetonide) Bar (0) (46 mg, 〇.〇5 mmol, 0.075 equivalent) and carbonic acid planer (767 mg, 2.35 mmol, 3.5 eq.) were added to a microwave vial. The bottle was capped and purged with argon. Degassed dioxane (4.5 ml) was added to the vial through the septum and the vial was again purged&apos; followed by backfilling with argon. The reaction was heated overnight at 157475.doc -98- 201211039 90 c in the sand. The crude reaction mixture was filtered through celite and used to contain 5% to 25. /. The gradient of decyl alcohol DCM (with a small amount of ammonium hydroxide added) was purified by chromatography to give 150 mg (63.7%). 2-(6-Tertibutyl-8-fluorobu-oxy-1H-pyridazine-2-yl)6 {5_[5-(3-decyloxy-azetidinyl 4-ylmethyl) _Pyridylamino] fluorenyl _6_ oxo-1,6-dihydro-pyridazin-3-yl}-phenylmethyl ester: 6-gas·4_[5-(3-methoxy- Azetidinium alkylpyridinium-2-ylamino]_2-fluorenyl-2-pyrazine-3-one (i〇〇mg, 0.29 mmob 1.0 equivalent), 2-(6-acetate) Tributyl-8-fluoro_1_sideoxy_1H_pyridazine_2_yl)_6_(4,4,5,5-tetramethyl_[1,3,2]-oxyborate -yl)-benzyl ester (247 mg '0.5 mm〇l, 1.75 eq.), bis(dibenzylideneacetone)|bar (82 mg, 0.014 mmol, 0.05 eq.), x-phos (13.6 mg, 0.028) Mmo Bu 0.10 eq.) and three times of dish acid (121 mg, 0. 57 mmol, 2.0 eq.) were added to a microwave vial. The bottle was capped and purged with nitrogen. Butanol (2.3 ml) and water (〇. 5 ml), and the bottle was again purged, followed by backfilling with nitrogen. The reaction was heated in a sand bath for 2.5 hours at 1 ° C. The crude reaction was filtered through diatomaceous earth and used 〇% to 25%. The DCM gradient of sterol is purified by chromatography and will contain the desired product. The dissolved fraction is combined with the material from which the acetate-based protecting group has been removed during the reaction to give 175 mg of the material (about 92%). Example 4 6-Terbutyl-8-fluoro-2-(2-hydroxyl) Base-3-{5-[5-(3-decyloxy-azetidin-1 -ylmethyl)-0 σ σ-2-ylamino]-1 -methyl-6- side Oxy-1,6-dioxin-pyridazin-3-yl}-phenyl)-2Η-.Torphyrin-1-one: 2-(6-third 157475.doc-99-201211039 base -8-fluoro-1-oxooxy-1H-pyridazine_2-yl)-6-{5-[5-(3-methoxy-azetidin-1-ylindenyl)-pyridine · 2-Aminoamino]_ι_indenyl_6_sideoxy-丨,6-dihydro-d.qin-3-yl}-benzal vinegar (175 mg, 0.26 mmol, 1.0 eq.) dissolved in 2.6 In THF, sodium hydroxide (1 3 ml 1.0 hydrazine aqueous solution '1.3 mmol, 5.0 eq.) was added dropwise. The reaction was stirred at room temperature overnight. After the next morning, the starting material was still present at 5 ° C. The reaction was heated for 2 h with no starting material residue. The mixture was diluted with ethyl acetate and water and the layers were separated and dried and evaporated and evaporated. In a vacuum oven And dried to give 75 mg (45.7 ° / 0) as a white powder of the desired product. nmR (300 MHz, DMSO-c?6) δ ppm 1.37 (s, 9 Η) 2.79 (t, 7=6.80 Hz, 2 H) 3-11 (s, 3 H) 3.37-3.44 (m, 2 H) 3.46 (s, 2 H) 3.77 (s, 3 H) 3.92 (t, J=5.85 Hz, 1 H) 4.40 (br.s., 2 H) 4.52-4.63 (m, 1 H) 7-40-7.62 (m, 5 H) 7.74 (d, 7=13.22 Hz, 1 H) 7.86 (s, 1 H) 8.15 (s,1 H) 8.48-8.55 (m,2 H) 9.36-9.44 (m, 1 H) . MS: (M+H)+=626. MP = 140-142 〇 C. Preparation 1-5 Example 5 157475.doc •100- 201211039

Use for the preparation of compounds! , the general procedure, the final methyl group is replaced by diazabicyclo[3.2.1]octane dihydrochloride to synthesize the methoxy azacyclobutane (tetra) acid salt in the first step and use 2·5# three Ethylamine converts the dihydrochloride to a free test to prepare 6_t-butyl_8_敦_2_(2_residue methyl_3_{ι_methyl-5-[5-(8-fluorenyl)- 3,8-diaza-bicyclo[3 2"]octyl_3_ylindenyl)-indole bite 2-ylamino]-6-sideoxy-1,6-dihydro-pyridazine_ 3-yl}-phenyl)_2Η-pyridazine-1-one. The resulting benzylamine intermediate was subjected to the remaining synthetic step to give 65 mg of the final product as a white powder. NMR (300 MHz, DMSO-d6) δ 9.38 (s, 1 Η), 8.48-8.54 (m, 2H), 8.10-8.17 (m, 1H), 7.86 (s, 1H), 7.74 (d, 7 = 13.22 Hz , 1H), 7.55-7.62 (m, 1H), 7.42-7.55 (m, 4H), 4.53 - 4.60 (m, 1H), 4.39 (br. s., 2H), 3.77 (s, 3H), 2.93 ( Br. s., 2H), 2.41 (d, 7=7.93 Hz, 2H), 2.15 (d, «7=10.20 Hz, 2H), 2.09 (s, 3H), 1.78 (d, /=4.91 Hz, 2H ), 1,62 (d, *7 = 6.80 Hz, 2H), 1.37 (s, 9H). MS: (M+H)+=665. MP = 162-165 〇 C. Preparation 1-6 157475.doc -101 - 1 201211039

Step 1. Preparation of ethyl 2-(6-apyridin-3-yloxy)-2-mercaptopropionate

Adding carbonic acid to a solution of 6-pyridin-3-ol (5 g' 38.6 mmol) and ethyl 2-bromo-2-mercaptopropionate (6.01 ml '40.5 mmol) in acetonitrile (50 mL)铯 (27 g, 83 mmol). The material was stirred vigorously for 48 hours. The mixture was dissolved in water (100 ml) and ethyl acetate (1 mL) and transferred to a sep. funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×5 〇 mL). The organic phases were combined, dried (MgSO4) filtered and evaporated. The crude material was purified by preparative HpLc (pluton; % g tube 157475.doc -102 - 201211039 column) by dissolving with 5-30 / 〇 gg ethyl ethyl ester / hexane to give a pale white-yellow fluid The desired product (6.78 g). (M+H)+=244 m/e. Step 2. Preparation of 2-(6-chloropyridin-3-yloxy)·2·methylpropanol

The solution of 2-(6-chloroη-pyridinyl-3-yloxy)_2-mercaptopropionic acid ethyl sulfonate (6.093 g, 25.0 mm 〇l) in anhydrous tetrahydrofuran (mL) was cooled to a nitrogen atmosphere. -2 (TC (acetonitrile/dry ice bath p over 1 hr., a lithium aluminum hydride solution (1.0 Μ in THF, 35 ml) was added by dropwise addition. The mixture was stirred at -2 〇t for 1 hour. The reaction was carefully quenched with water (0 73 ml). The mixture was stirred for 10 min then 5% aqueous sodium hydroxide (1.34 ml) was added with stirring for 1 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> After 10 minutes, magnesium sulfate was added, and the filter material was plugged with diatomaceous earth under full rinsing with tetrahydrofuran. (Note that the aluminum salt was then stirred in dichloromethane (5 〇ml) and filtered through diatomaceous earth to give another portion. The product was stripped on a rotary evaporator to give the desired product (4.843 g) as a semi-viscous brown oil. (M+H)+=202 m/e. Step 3. Preparation 2-(6-gas Pyridin-3-yloxy)-2-mercaptopropanal 157475.doc -103- 201211039

The dried flask (5 〇 ml, round bottom) containing anhydrous di- methane (13 ml) was cooled to -78 C (dry ice/acetone bath) under argon atmosphere. Ethylene dioxane (0·23 ml ' 2.67 mmol) was added followed by the addition of anhydrous diterpenoid (0.3 1 ml '4.3 1 mmol) via dropwise addition. The mixture was dispensed for 1 , minutes, followed by a slow dropwise addition of 2-(6-chloropyranyl-3-yloxy)_2-methylpropanol (451 mg '2.06 mmol) [dissolved in Dioxane (4 ml)]. The cooled solution was searched for 30 minutes, then triethylamine (5 min, &lt;RTI ID=0.0&gt; The mixture was stirred and warmed to ambient temperature over 1 hour. Saturated sodium bicarbonate solution (20 ml) was added, and a second gas (20 ml) was also added. The material was transferred and shaken in a separatory funnel. The two gas phase was collected and washed with a brine solution (25 mL). The aqueous phase was back-extracted with dichloromethane (2 x 20 mL) and the organic phases were combined, dried over magnesium sulfate, filtered and evaporated. With a short crucible tube column (20 g), use 30 ° /. Ethyl acetate / hexanes were isolated by filtration to purify the material to give the product as a pale yellow oil (361 mg) (M+H) += 200 m/e 〇 Step 4. Preparation of 2-(6-pyridine- 3-yloxy)-N,N,2-trimethylpropan-1-amine

157475.doc 201211039 to 2-(6-chlorooxy)_2•methylpropene (354 ̄, ι 77 mmol) and sodium triethoxy borohydride (94 〇, 4 43 丨) Glacial acetic acid (0.81 nU, 14.2 mmol) and 2 M dimethylamine solution (14 2 mi, 28 4) were added to the large-capacity microwave tube of anhydrous methyl chloride (4 ml) / gluten.

Mmmol. The tube was capped in a tetrahydrogenate and heated to 50 C (oil) under vigorous mixing for 6 hours. The mixture was cooled to ambient temperature and the contents were poured into a saturated aqueous solution of sodium hydrogencarbonate (3 liters of a seperate funnel. Dichloromethane (3 〇ml) was added and the mixture was shaken. Under the service, the transitional contents were embolized by Shixiazao. The liquid was collected and washed with saline solution (40 ml). The second gas was collected and the aqueous phase was back-extracted with two gas (2 x 40 mL). The organic phases were combined, dried over magnesium sulfate, filtered and evaporated, and purified by preparative thin layer chromatography (2 s) with 1.8% methanol/di-methane methane, followed by 2 6% methanol / The gas methane re-developed the disk, and the product tape was collected to obtain the desired material (255 mg) in the form of a light yellow oily oil which solidified slowly upon standing. (M+H)+=229 m /e. Step 5. Preparation of 4-Mo-6-chloro-2-indolylindole-3(2H)-one

W2 human N Ο &quot; ^ λ^Ν- to 2-(6-chloroacridin-3-yloxy)_Ν, hydrazine, 2-3-trimethylpropanylamine (255 mg, 1,11 mmol) in anhydrous In a solution of tetrahydrofuran (6.6 ml), 157475.doc -105 - 201211039 added dicyclohexylphosphino)biphenyl (78 mg, 0.22 mmol), ginseng (diphenylmethyleneacetone) dipalladium (0) ( 102 mg, 0.11 mmol). The mixture was vacuum degassed&apos; and placed under an argon atmosphere. A lithium bis(tridecyldecyl) aminide solution (3.34 ml' in tetrahydrofuran) was added and the tube was sealed and heated to 75 ° C (oil bath) overnight with vigorous stirring. The mixture was cooled to ambient temperature and the contents were poured into a sep. funnel containing a saturated aqueous solution of ammonium chloride (25 ml). Dichloromethane (3 〇 ml) was added and the mixture was shaken. The organic phase was collected and the aqueous phase was back extracted with dioxane (4 x 5 〇 mL). The combined dichlorohydrazine phases were dried over magnesium sulfate, filtered and stripped. The material was purified by preparative thin layer chromatography (2 disks) by dissolving with 8% methanol/two gas. The product was collected in a red-brown viscous oil (229 mg). Substance "Knowledge: As is" is used in the next step. Step 6. Preparation of 6-gas-4-(5-(1-(dimethylamino))-2-methylpropan-2-yloxy).pyridin-2-ylamino)_2-mercaptopurine Pyrazine_3(211)-one

Q - 4-Di-6-chloro-2-methylpyridazine_3(2H)_ _ (282 mg, 1.26 _〇1), 5-(1_(didecylamino)-2-mercaptopropyl -2-yloxy)tI ratio bite_2_amine (203 mg, 0.97 mmol), Xantphos (84 mg, 〇·15 mm〇1) and carbon 157475.doc 201211039 acid planer (1.11 g, 3 39 mm〇 1) A solution of anhydrous dioxane (6 6 ml) was degassed under vacuum in 4 Torr and placed under argon atmosphere. To this mixture was added ginsole (n-methylideneacetone) di Is (0) (67 mg, 0.073 mmol), and the vacuum degassing cycle was repeated. At 9 〇. The material was heated overnight under vigorous stirring at [: (oil bath). The flask was cooled to ambient temperature and the contents were filtered through a sputum-filled plug under full flushing with dioxane. The volatiles were stripped and by using 6 first. The crude oil was purified by preparative thin layer chromatography (4 disks) by dissolving the alcohol/dichloromethane and then re-expanding with 8% methanol/dichloromethane. The product tape was collected to give the desired material (196 mg) as a pale powder. (M+H)+=352 m/e.

Pd(dba)

Xphos

To the microwave reaction flask was added 2-(6-t-butyl-8-fluoro-1-oxo- 1H-oxazin-2-yl)-6-chloro-phenylmethyl acetate (329 mg, 0.8. 18 mmol), bis (pinacol root) two sides (416 mg, 1.637 mmol), KOAc (241 mg, 2.454 mmol) and Xph〇s (39 mg, 0.0818 mmol) and two-week hospital (4 mL). Argon was bubbled through for 5 minutes, followed by the addition of Pd(dba)2 (24 mg, 0.0409 mmol). The tube was sealed and heated to 60 ° C for 18 hours. The reaction mixture was then diluted with EtOAc (5 mL) and washed with NaHC. The organic phase was then concentrated and purified on a silica gel column eluting with 2% EtOAc to afford 2-(6-t-butyl-8 - Too 嘻-2-157475.doc .107- 201211039 base)-6-(4,4,5,5-tetradecyl_[ι,3,2]dioxaboron-2-yl)_benzamide Ester (33 〇 mg, 8 1 %) 0 Step 7. Preparation of acetic acid 2-(6-t-butyl _8_fluoro_丨_ oxaoxypyridazine·2_yl)_6_ {5-[5-( 2-Didecylaminodiindenyl-ethoxylated acridine-2-ylamino]_ 1-indolyl-6-yloxy-1,6-dihydro-pyridazine_3_yl b Phenyl phthalate

The flask was fed with 2-(6-tert-butyl_8_fluoro-indole-oxetazine- 2(1H)-yl)-6-(4,4,5,5-tetra-yl) -^: Dioxaboron-2-yl)phenyl phthalate (391 mg, 〇·5 5 mmol), 6-gas-4-(5-(1-(didecylamino)-2-methyl) Prop-2-yloxy)pyridine_2-ylamino)_2-methylpyridazine_3(211)-one (15〇mg 0·43 mmol), X_phos (31 mg, 〇〇6 curry 1 And tripotassium phosphate (199 mg 〇·94 mm〇i)e The mixture was dissolved in n-butanol (28^) and water (0.67 ml), and vacuum degassed and placed under an argon atmosphere. To this mixture was added bis(dibenzylideneacetone)palladium (i7 mg, 〇.03 mmol)' and the vacuum degassing cycle was repeated. Heat the material under vigorous stirring on an argon atmosphere for 2.5 hours under argon (: (oil bath). Cool the flask to ambient temperature' and dissolve the contents in water (35 ml) and ethyl acetate (35 ml) Transfer the contents to a separatory funnel and shake. Collect the organic phase and wash with water 157475.doc -108 - 201211039 (35 ml). Extract the aqueous phase with ethyl acetate (2x30 ml) and combine The organic phase was dried (MgSO.sub.4) filtered and stripped. The residue was purified by preparative thin layer chromatography (3 EtOAc) eluting with &lt The desired product (and some deacetylated products) (3 j 2 mg). (M+H)+=684 (642) m/e. Step 8. Preparation of 6-t-butyl-2-(3) -{5-[5-(2-Didecylaminodifluorenyl-ethoxy)-pyridin-2-ylamino]-1-methyl-oxo-oxime, 6-dihydro-pyridazine _3_ base}-2-methyl-phenyl)-8-fluoro-2H-pyridazine-1-pyrene

To 2-(6-t-butyl-8-fluoro-1-oxooxy 2,(ih)-yl)-6-(5-(5-(1-(dimethylamino)) _2_Methylpropyloxy)ti-pyridylamino)_1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-benzoin (292 mg, 0.43 Add 2^^ sodium hydroxide solution (2.5 m b 5 mmol) to a solution of dioxane (1.5 ml). The flask was heated at 5 (TC (oil bath) under vigorous stirring under argon for 3 hours. The material was cooled to ambient temperature and the contents dissolved in water (25 ml) and dichloromethane (50 ml) And transferred to a separatory funnel and shaken off. The organic phase was collected and washed with 50% diluted brine (25 mi) 157475.doc -109- 201211039. The aqueous phase was back extracted with dichloromethane (2 x 40 ml). The combined organic phases were dried (magnesium sulfate), filtered and stripped. Dissolved by 6% methanol/two gas, followed by 8% methanol/dioxane and 11 〇/〇methanol/secondary The resulting product (72 mg) was obtained as a pale yellow-white solid. (M+H)+=642 m/e. 4 NMR (300 MHz, gas-like?) δ ppm 1.28 (s,6 Η) 1.42 (s,9 Η) 2.40 (s 6 H) 2.51 (s , 2 H) 3.90 (s, 3 H) 4.42 (s, 2 H) 6.90 (d, J=9.〇6

Hz' 1 H) 7.33 (dd, J=8.69, 3.02 Hz, 1 H) 7.41-7.72 (m,5 Η) φ 8.09 (d, /=3.02 Hz, 1 H) 8.20-8.35 (m, 2 H) 8.53 (Ss ! h). Preparation 1-7 Example 7

Using a general procedure as described for compound I-4, using azetidin, a sulfoxy azetidine hydrochloride in the V step, and eliminating the use of a triamine to prepare a nitrogen heterocycle. Small base _ _ _2 基 胺 胺 胺 胺 胺 , 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 1,. The resulting benzylamine intermediate was subjected to the remaining synthesis step, and the MM% was added to 35 mg of the final product as an off-white powder. 157475.doc •110* 201211039 NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.47-8.56 (m, 2H), 8.15 (s, 1H), 7.86 (s,lH), 7.74 (d , 7=13.22 Hz, 1H), 7.40-7.63 (m, 5H), 4.51-4.62 (m, 1H), 4.40 (br. s., 2H), 3.77 (s,3H), 3,40 (s, 2H), 3.06 (t, /=6.80 Hz, 4H), 1.92 (five peaks, /=6.89 Hz, 2H), 1.37 (s, 9H). MS: (M+H)+=596. MP = 160-163 ° C. Preparation 1-8 Example 8

Prepare 6 third butyl using the general procedure described for the preparation of compound j_4

Benzyl-2-{3-[5-(5-dimethylaminomethyl-acridine-2-ylamino)__methyl-6_ oxo-1,6-dihydro-pyridazine _3_基]_2_hydroxyindole __phenyl 88_ι_2Η•呔 -1, 'but because (6-chloro-pyridyl-m-ylmethyl)-didecyl-amine is commercially available, so it is omitted The first step. This compound was subjected to the remaining synthetic step to give 120 mg of an off-white product as an off-white powder. H NMR (3〇〇MHz, DMSO-36) δ ppm 9.4G (s,! m H) 8.47-8.57 (m,2 H) 8.15 (s,1 H) 7.86 (s, 1 H) 7.74 (d jn 9 M , 1,J~13'2 Hz,1 H) 7.56-7.65 (m,1 H) 7.42-7.56 (m,4 H) 4 /i , )4·52-4·61 (m,1 H ) 4.40 (br s 2 H) 3.77 (s,3 H) 3.34-3.40 u a ^ 5 } (, 2 H, obscured by DMSO water peak) 2 1〇(s, 157475.doc -Ill - 201211039 6 Η) 1.37 (s,9H) » MS: (M+H)+=584. MP = 170-174 ° C. Preparation 1-9

8-(6-nitro.pyridin-3-yl)_3 8_diazabicyclo[3 2(1)octane-3-pyruic acid third vinegar + hnq&gt;^x __ · will be in the 'under the dish' Diethylamine (6.87 mL, 49·3 mmol) was added to 5-fluoro-2-nitropyridine (700 mg, 4·93 _〇1) and (1R 5S) 3 8 diazabicyclo[3.2.1] The tributyl butyl benzoate (j 〇 5 g, 4 93 〇 1) was mixed in a solution of 8 in DMS. The reaction mixture was heated to 80 ° C for 2 hours. After the cold portion was cooled to room temperature, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and water (3 hexanes), dried over anhydrous sodium sulfate, filtered and concentrated in the air to obtain 21 g (73 5%). 8_(6nitropyridyl 157475.doc -112· 201211039 pyridine-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-decanoic acid tert-butyl ester as a yellow solid. 8-(6-Aminopyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl vinegar :do - Η心

To 3-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (330 mg ' 987 μιηοΐ) in 10 ml of methanol 10% palladium on carbon (10 mg) was added to the solution. The reaction mixture was hydrogenated under 50 psi of hydrogen for 2 hours. The reaction mixture was filtered through a pad of celite and concentrated to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&& Octadecyl 3-octane-3-carboxylate. This product was used in the next step without further purification. (1R,5S)-8-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydro-indole-4 -ylamino)pyridin-3-yl)-3,8-diazabicyclo[3'2.1]octane-3-carboxylic acid tertidine

This reaction was carried out under conditions similar to those described in the above Step 6 of Preparation Example 6. After the treatment, the product was purified by silica gel preparative HPLC using a gradient of 2% to 8% decyl alcohol / dioxane. This gave the desired product (275 mg, 62.4%) as a pale yellow solid (yield: Μ + Η) + = 447·2 m/e. 8-(6-(6-(2-(Ethyloxymethyl)-3-(6-tert-butyl-8-fluoro-1-yloxy)-pro-Qin-2(1H)-yl Phenyl)_2_methyl-3-oxooxy-2,3-dihydrokin-4-yl 157475.doc • 113· 201211039 Amino)pyridin-3-yl)-3,8-diaza Heterobicyclo[3.2.1]octane-3-carboxylic acid diced vinegar

This reaction was carried out extensively under the conditions described in the above step 7 of Preparation Example 6. Containing (lR,5S)-8-(6-(6-chloro-2-methyl-oxo- 2,3-dihydropyridazin-4-ylaminobipyridin-3-yl)-3 with nitrogen , 8-diazabicyclo[3 2 ^ 辛烧-3 - 曱Jing third vinegar (1〇〇mg, 224 μιηοΐ), acetic acid 2_(6_ _ butyl-8-fluoro-1-side oxygen Pyridazine-2(1Η)-yl)-6-(4,4,5,5-tetramethyl 1,3,2, dioxaboran-2-yl)benzyl ester (114 mg, 224 μηιοί ), xPh〇s (10.7 mg, 22.4 μπιοί) and potassium phosphate (119 mg, 559 μηιοί) of 7 ml of dioxane/water (9:1) were degassed for 10 minutes, and bis(diphenylmethyleneacetone) was added. Sharp (0) (6.42, 11.2 μηιοί). The reaction mixture was heated to 100 ° C for 2 hours. After treatment, it was purified by silica gel preparative HPLC using a gradient of 5% to 70% ethyl acetate / hexane. The desired product (105 mg, 60.3%) was obtained as a pale yellow solid. (M+H)+= 779 m/e. 8-(6-(3-(6-tributyl) -8-Ga-1-indolyl oxime-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl Amino group.. Ratio 157475.doc •114· 201211039 biting-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid Tributyl vinegar

This reaction was carried out under conditions similar to those described in Step 8 of Preparation 1-6 above. After treatment, the product was obtained as a pale yellow powder (90 mg, 90.6%). (M+H)+=737 m/e. Example 9 2-(3-(5-(5-(3,8-diazabicyclo[3.2.1]oct-8-yl).pyridin-2-ylamino)-1-methyl-6 -Sideoxy-1,6-dihydrodazo-3-yl)-2-(sulfenyl)phenyl)-6-tert-butyl-8-fluoropyridazine-1(2H)-one

157475.doc •115· 201211039 8-(6-(3-(6-T-butyl)" with dioxane (i〇mL) containing 50〇/〇 trifluoro acid 8-fluoro-1-oxophthalazine_2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazine -4-ylamino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-butyric acid tert-butyl ester (90 mg, 122 μηιοί) removed B0C 'continued 2 hours. The reaction mixture was concentrated to dryness then partitioned between ethyl acetate and saturated sodium hydrogen carbonate. The organic phase was dried over sodium sulfate, filtered and concentrated. The product was collected and further purified by crystallization from hot isopropyl acetate / hexane. The crystalline product was collected by filtration to give the desired product (53 mg &apos; 68.1%) as pale brown powder. (M+H)+=638 m/e. NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1 Η), 8.49 (d, "7=2.44 Ηζ, 1H), 8.31-8.35 (m, 1H), 7.90 (d, 7 = 2.44 Hz, 1H) , 7.85 (d, •/=1.95 Hz, 1H), 7.73 (d, “7=11.71 Hz, 1H), 7.49-7.55 (m, 1H), 7.43-7.48 (m, 2H), 7.37 (d, J =8.79 Hz, 1H), 7.27 (dd, 7=2.93, 9.27 Hz, 1H)} 4.48-4.56 (m, 1H), 4.38 (d, /=11.23 Hz, 3H), 4.04-4.15 (m, 2H) , 3.69-3.79 (m, 3H), 2.93 (d, 7=12.20 Hz, 2H), 2.42-2.46 (m, 2H), 1.82-1.93 (m, 4H)} 1.36 (s, 9H). Preparation 1-10 Step 1. I57475.doc 201211039

Add 6-amino nicotinic acid methyl ester (170 mg, 1.12 mmol '1.00 equivalent), 4-bromo-6-chloro-2-methylpyridazine-3(2H)-one to a 15 mL microwave vial ( 250 mg, 1.12 mmol, 1.00 equiv), Cs2C〇3 (128 g, 3 92

Methyl ** (d); g) and xantphos (97.1 mg, 168 μιηοΐ, 0.15 equivalent) of dioxan (8 ml). The reaction was purged with argon and pd.sub.2 (dba)3 (&lt;/RTI&gt;&gt; The bottle was capped and heated in a microwave at 90 ° C for 30 minutes ^ t = 30 minutes, LC-MS showed incomplete reaction with SM residue. The reaction was heated for an additional 30 minutes at 12 Torr. The sample has solidified. The crude mixture was dissolved in DCM and stripped to give a dark brown oily solid. The residue was dissolved in DCM and washed with water. The aqueous layer was back extracted with DCM (2 x 50 mL). The combined organic layers were washed with EtOAc EtOAc m. LC-MS of the crude organic phase showed predominantly product. The crude material was wet milled with DCM and cooled. The brown solid was transferred and washed with a minimum of cold DCM. The solid was dried under vacuum to give 158 mg &amp; /〇. 1H NMR (in DMSO-d6) was obtained with the desired product. MS (m+l)=295.0 〇 Step 2. 157475.doc 117- 201211039

Add 6-(6_ gas sulfhydryl_3_sideoxy-2,3-dihydropyridazin-4-ylamino)methylnicotinate (153 mg, 519 μηη〇) to a 15 mL microwave vial. 1, ι 〇〇), 2-(6-t-butyl-8-fluoro-1- oxetazine-2-(1Η)-yl)_6_ (4,4,5,5-tetramethyl acetate) Benzyl-1,3,2-dioxaboronic acid-2-yl)phenyl benzoate (3 34 mg, 675 μιηοΐ' 1.3) and Cs2C03 (592 mg, 1,82 mmol, 3.5 equivalents) Hospital (5 ml) and water (0.5 m丨). pdDCl2 (DPPF) (42.4 mg ' 51.9 μπιοί ' 0.1 equivalent) was added and the suspension was purged with argon. The bottle was capped and heated in a microwave at 120 °C for 30 minutes. At t = 30 minutes, LC-MS showed the reaction was completed. Dilute with pCM and pass through the stone. The yellow filtrate was stripped in the air to give a brown solid. This material is not very soluble in DCM. The crude material was used as such in the subsequent hydrolysis. Step 3.

In a 250 mL round bottom flask, 6-(6-(2-(ethyloxyindenyl)_3_(6_t-butyl-8-fluoro-1-oxophthalazine-2(1H)- Methyl)nicotinate (325 mg, 519 157475.doc •118-201211039 μπιοί, In combination with dioxane (1 〇mi) and 1 μ LiOH (3 ml), a yellow solution containing a small amount of insoluble fine particles was obtained. LC-MS showed the reaction was completed at 25 <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; The phases were re-extracted with EtOAc (2×25 mL). EtOAc (EtOAc m. Powder, yield 12%. 1H NMR (in CDC13) was consistent with the desired product. ms (ml) = 569. Example 10 6-{6-[3-(6-t-butyl-8-fluoro-1- side oxy-1H-pyridazine-2_yl)_2-hydroxymethyl-phenyl]-2-methyl-3-oxo-2,3·dihydro-pyridazin-4-ylamino}- N,N-monomethyl at test amine

Step 4. '6-(6-(3-(6-T-butyl-8-fluoro-1-yloxypyridazine-2(1H)-yl)-2-) in a 50 mL round bottom flask (hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydro-calling 4-ylamino) final acid (34 mg, 59.6 μιηοΐ, 1.00 equivalent), inclusive 2 dimethylamine THF (38.7 μΐ, 77.5 μηι〇1, 1.3 eq.) and Hunig's base (23.1 mg, 31.2 μΐ, 179 μηιοί, 3 equivalents) combined with DMF (1 ml) Yellow solution. HATU (27.2 157475.doc • 119·201211039 mg, 71·5 μιηοΐ, 1.2 eq.) was added, and the reaction mixture was stirred at 25 ° C for 21 hours. At t = 21 hours, LC-MS showed the reaction was completed. The reaction mixture was diluted with H20 and DCM. The two phase mixture was filtered and the aqueous layer was back extracted with DCM (3 x 20 mL). The combined organic layers were washed with water, dried EtOAc EtOAc EtOAc The crude material was purified by flash chromatography (EtOAc, EtOAc:EtOAc The product was dried under vacuum to give 11 mg of a white crystalline solid, yield 31%. 1H NMR (in CDCI3) was consistent with the desired product. MS (m+l) = 598. Preparation 1-11 Example 11

To 5-(difluoromethylindol-2-amine (146 mg, 0.90 mmol), 4-filled 2-mercaptopyridazine-3(211)-one (2 mg, 〇·9〇mmol ), carbonic acid (1.02 g ' 3.13 mm〇i) and 4,5_bis(diphenylphosphino)_9,9-dimethylxanthine (77.7«^, 0.13111111〇1) in dioxane ( Add bis(diphenylarbenium acetonide) dipalladium (0) (61.5 mg, 0.07 mm 〇1) to the solution in 10.0 „11), and purify the reaction mixture with an atmosphere (3 χ), then heat to 90 °c. The mixture was cooled for 2 hours. The mixture was cooled, diluted with methylene chloride and water (50 mL), and the layers were separated. The aqueous phase was extracted with dioxane (2×25 mL). The organic phase was combined and dried over MgSO. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc. Gas-2-mercapto-4-(5-trifluoromethyl-pyrazine-2-amino)-2H-pyridazin-3-one (197 mg, 72%): LC/MS of C10H7C1F3N5 m/e calculated [M] + 305.03, observed 305.9. Argon was bubbled through 6-chloro-2-methyl-4-(5-(trifluoro) Mercapto)pyrazin-2-ylamino)pyridazin-3(2H)-one (109 mg, 0.36 mmol), 2-(6-t-butyl-p-oxypyridazinyl)-6-( 4,4,5,5-tetramethyl-1,3,2-dioxaboromid-2-yl)benzyl ester (264 mg, 0.54 mmol), potassium phosphate (189 mg, 〇·89 mmol) and 2-Dicyclohexylphosphino 2,, 4,6,-triisopropylbiphenyl (17.0 mg, 〇.〇4 mm〇i) in n-butanol (4 ml) and water (1 ml) The solution was continued for 10 minutes. To this solution was added bis(dibenzylideneacetone)dipalladium(0) (10.3 mg, 0.02 mmol), and the resulting mixture was heated to 100 C for 2 hours. The mixture was cooled and then Pour into a saturated ammonium chloride bath. Extract the mixture with di-methane (2×1 〇〇η^), combine with φ machine phase and dry with Mgs 〇 4. Filter the mixture and evaporate, and dissolve the residue in two To the solution was slowly added 2 liters of lithium hydroxide solution (0.5 mL), and the mixture was stirred overnight at room temperature. The resulting mixture was poured into a saturated gasification solution. Methane (2χ15〇ml) extract the mixture and combine the organic phases The mixture was dried over MgSO.sub.4, and the residue was purified by flash chromatography eluting with EtOAc EtOAc EtOAc. / Recrystallized from monochloromethane to give 6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-indenyl-6_yloxy_5_ 157475.doc •121 as a white solid. . 201211039 (5-Triethyl-methyl-°°Qin-2-ylamino)-1,6-dihydro-d-Chent-3-yl]-phenyl}-2H- °Tai-1- Ketone (65 mg, 31°/. ): Mp 25 0-254°C; LC/MS m/e calculated for C29H25F4N703 [M+H]+ 596.20, observed 596.3 ; !H NMR (DMSO-d6) δ: 10.38 (s, 1H), 8.71 -9.08 (m, 2H), 8.43-8.66 (m, 2H), 7.68-8.02 (m, 2H), 7.38-7.65 (m, 3H), 4.54-4.76 (m, 1H), 4.40 (br. s. , 2H), 3.82 (s, 3H), 1.38 (s, 9H).

Process A Preparation 1-12 φ

This example illustrates the "6-second butyl-8-say-2-(3-{5-[5-(2-propionyl-1,1-didecyl-ethoxy)-D ratio. 2-Aminoamino]-1-indolyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxyindolyl-phenyl)-2H-pyridazine-1- Synthesis of ketones. Step 1 · Preparation of 2-(6-Amino-pyridin-3-yloxy)-2-indolyl-propionic acid ethyl ester 157475.doc -122- 201211039

Anhydrous acetonitrile (6 g) containing 6-amino carbonitrile-3-ol hydroformate (2 g, 10_5 mmol) and ethyl 2-bromo-2-methylpropanoate (2.04 g, 10.5 mm 〇l) Ml) A flask of the solution (10.7 g, 33 mmol) was added to the flask and the mixture was stirred under argon for 16 hours. Water (6 〇 mi) and ethyl acetate (60 ml) were added and the material was shaken in a separatory funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×50 ml). The combined organics were dried <RTI ID=0.0> (M+H) = 225 m/e ° Step 2. Preparation of 2-[6-(6-Gas-2-indolyl-3-oxo-2,3-dihydro-pyridazin-4-ylamine) Ethyl)-pyridin-3-yloxy]-2-methyl-propionic acid ethyl ester

Evacuation of 2-(6-aminopyridin-3-yloxy)-2-methyl-propionic acid in ethyl acetate (1.365 g, 6.09 mmol), 4-bromo-6-hexane-2-indole under vacuum Base 嚏〇 3 -(2H)-one (1.77 g, 7.91 mmol) '4,5-bis(diphenylphosphino)-9,9-dimethyldibenzo. bottom. A flask of sodium (528 mg, 0.913 mmol) and cesium carbonate (6.94 g, 157475.doc -123 - 201211039 21.3 mmol) in anhydrous dioxane (6 〇mi) was refilled with argon (3 repetitions). Add gin (diphenylmethyleneacetone) dipalladium (〇) (418 Claw, 0.457 mmol) and vacuum the flask under vacuum and backfill with argon (3 repetitions). The flask was placed in an oil bath heated to 9 (rc) and stirred under argon atmosphere for 16 hours. The flask was cooled to ambient temperature and the filter material was plugged with diatomaceous earth under extensive flushing with dioxane. The volatiles were concentrated, and the residue was purified eluting eluting eluting eluting eluting eluting with ) += 367 m / e. Step 3. Preparation of 6_gas-4_[5-(2-hydroxy- ΐ, ι dimethyl]-2- from ethoxy)-»-pyridin-2-ylamine Mercapto-2H-pyridazine-3-ketone

Soil 2,3-dihydro-pyridazin-4-ylamino)-:acetate (1.23 g ' 3.35 mmol, ml), and cooled under nitrogen for 1 min, added dropwise via dropwise ' 4.69 mmol, ι·〇μ, while maintaining the bath temperature of about _2 〇. Hey. Dissolve 2-[6-(6-chloro-2-methyl_3_sideoxy-2,3_di"pyridin-3-yloxy]_2-fluorenyl-propionic acid ethyl ester 1.00 equivalent) In anhydrous THF (25 ml) and up to 3 ° C (dry ice / acetonitrile cooling bath). A solution of lithium aluminum hydride (4 7 ml, 4, 69 in THF) was slowly added over 1 min. The mixture was stirred for 1 hour, the same, 157475.doc •124-201211039 The reaction was carefully quenched by the addition of water (0.1 and stirred for 10 minutes to ambient temperature. Then 5% aqueous sodium hydroxide (0.19 ml) was added and the mixture was mixed. 10 minutes. Add water (0.19 mI) and continue to stir for 1 minute. Finally add magnesium sulfate, and embed the filter material through diatomaceous earth with sufficient washing with tetrahydrofuran. Concentrate the material to about one on a rotary evaporator.

The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2 ml). The combined organics were dried over sulphuric acid, dried and concentrated in vacuo. The desired product (1.041 g) was obtained as a pale yellow-brown solid. (M+H)+=325 m/e. Step 4. Prepare acetic acid 2-〇r&lt;inosyl-1H-pyridazine-2_yl)-丨{5_[5-(2-hydroxy-1,1-dimethyl-acetamidine 6#丨Window 1, ethoxy)-pyridine·2·ylamino]-1-methyl 6-sideoxy-1,6-diindole-pyridazine_3_yl}

Methyl, azine in a similar manner to [5-(2-hydroxy-1,1-dimethyl-ethoxy) 2 in Step 7 of Examples 1-6, but using 6-chloro-4-2H ~°Dazin-3-one in place of 6-gas_4-[5&lt;2_ _疋'2'-ylamino]_2·indolyloxy-pyridin-2-ylamino]_2-methyl The amino group-1,1-dimethyl-ethyl, ketone is used to carry out this reaction 157475.doc -125- 201211039 should be. After processing, by using 5. /. The product was purified by preparative thin layer chromatography (3 disks) by decyl alcohol/di-gas methane elution. This gave the desired product as a light brown viscous oil (as well as some of the succinated product) (4 〇〇mgp (m+h) + = 657 m/e. Example 12 Step 5. Preparation 6 - Second butyl -8-fluoro-2-(3-{5-[5-(2-amino-1,1-didecyl-ethoxy)-pyridin-2-ylamino]-1·methyl_6 -Sideoxy-i,6-dihydro-pyridazine_3_ kib 2-pyridyl-phenyl)-2H-halo-1-one

This reaction was carried out under conditions similar to those described in Step 8 of Examples 1-6. After the treatment, the product was purified by preparative thin layer chromatography (3 disks) by dissolving with 2% sterol/diqimethane. The disk was then re-expanded with 3% methanol/diqi methane and 5% decyl alcohol/dioxane. This gave the desired product (226 mg) as a pale yellow solid. (M+H)+=615 m/e. NMR (300 MHz, gas simulation _ύ〇δ ppm 1.27 (s,6 H) 1.43 (s,9 H) 2.14 (t, /=6.42 Hz, 1 H) 3.61 (d, 7=6.04 Hz, 2 H) 3.90 (s, 3 H) 3.91-3.95 (m, 1 H) 4.42 (d, J=6.80 Hz, 2 H) 6.92 (d, 7=8.69 Hz, 1 H) 7.32 (dd, 7=8.88, 2.83 Hz , 1 H) 7.43-7.54 (m, 3 H) 7.57 (t, 157475.doc -126- 201211039 «7=7.90 Hz,1 Η) 7.63-7.70 (m, 1 Η) 8.09 (d, 7=3.02 Hz , 1 H) 8.24-8.32 (m, 2 H) 8.55 (s, 1 H)

Process B Preparation 1-13

Cl

This example illustrates "2-(3-{5-[5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-° ratio π-2-1-amine 1-methyl-6-o-oxy-1,6-diaza-.dazin-3-yl}-2-hydroxyindolyl-phenyl)-6-tert-butyl-8-fluoro Synthesis of -2Η-pyridazin-1-one. Step 1. Preparation of 2-[6-(6-chloro-2-indolyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-pyridin-3-yloxy] -2-mercapto-propionaldehyde 157475.doc -127- 201211039

6-Gatro-4-(5-(1-hydroxy-2-methylpropan-2-yloxy)acridin-2-ylamino)-2-mercaptopyridazine_3_(21·!) The ketone (965 mg, 2.97 mmol) was dissolved in a mixture of tetrahydrofuran (25 ml) and dioxane (15 ml). To the suspension was added Dess-Martin Periodinane (1.64 g, 3.86 mmol) and the flask was capped and allowed to mix for 4 minutes. Sodium bicarbonate saturated aqueous solution (5 〇 m1), 10% aqueous sodium thiosulfate (50 ml) was added sequentially, and the mixture was vigorously stirred for 15 minutes. Ethyl acetate (50 ml) was added and the contents were shaken in a separating funnel. The organic phase was collected and washed with brine (50 mL). Set the 酉 酉 乙 曰 且 且 and use a gas simmer (2 x 40 ml) to back extract the aqueous phase. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The product was purified by wet trituration in EtOAc-EtOAc (EtOAc) (M+H)+=323 m/e. Step 2. Preparation of 4-Bu(2-azetidinyl)-]didecylethoxy)·β ratio bit_2·ylamino]methanol methylserazine I ketone 157475.doc 201211039

2-[6-(6-Gaxo-2-indolyl-3-sideoxy-2,3-dihydro-pyridazin-4-ylamino)- 〇-- 3-Hydroxy]-2-methyl-propanyl (188 mg, 0.582 mmol) was dissolved in di-methane (2.5 mL). Triethylenesulfonate sodium sulfonate (309 mg, 1.46 mmol) and acetic acid (〇.1^75 mmol) were added, followed by cooling the flask in an ice bath under a nitrogen atmosphere. Azacyclobutane (0.24 ml, 3.49 mmol) was added and the flask was sealed. The flask was placed in an oil bath heated to 50 C and allowed to fall for 16 hours. The mixture was cooled to ambient temperature and dissolved in dichloromethane (50 ml) and saturated aqueous sodium bicarbonate (50). The material was transferred to a separatory funnel and shaken. The organic phase was collected and diluted with 50 ° / 〇 (50 ml) Washing. Collect the dichlorohydrazine phase and back-extract the aqueous phase with dichloromethane (2 x 40 ml). Dry (MgSO4) combined organic phase &lt; Loading onto two preparative TLC trays and dissolving in 8% methanol/dichloromethane. The product strips were collected to give the desired product as a pale white-brown powder (139 mg) » (Μ+Η)+=364 m/ e. Step 3. Preparation of 2-{5-[5-(2-azetidinyldimethoxy-ethoxy)-pyridin-2-ylamino]-1-methylxyloxy-hydrazine ,6_Dihydro-pyridazine_3_kib6·(6-t-butyl-8-fluoro-1-yloxy·1H-pyridazine-2-yl)·benzoquinone 157475.doc - 129- 201211039

Γό^Γό Preparation of acetic acid using the general procedure described in Step 7 of Preparations 1-6 2{{· [5-(2-acetonine, 1-yl-1,1-didecyl-ethoxy Base)-Acridine-2-ylamino]_1_fluorenyl-6-o-oxy-1,6-dihydro-pyridazin-3-yl}-6-(6-tert-butyl- 8- H-1-Sideoxy-1Η-pyridazine-2-yl)-benzoin. After the treatment, the material was purified by preparative TLC (3 trays) eluting with 8 〇 / 〇 methanol / dimethyl methane to give the desired product as a light brown viscous oil (238 mg) ^ (m+H) +=696 m/e. Example 13 Step 4. Preparation of 2-(3-{5-[5-(2-azetidin-1-yl-l,i-didecyl-ethoxy)- 0-but-2-yl Amino]-i-fluorenyl-6-o-oxy-1,6-dihydro-indole-3-yl}-2-hydroxyindolyl-phenyl)-6-tert-butyl-8-fluoro _2H-phthalazin-1-one

Preparation of 2·(3-{5_[5-(2-azetidin-1-yl-1,1-didecyl-ethoxy) using the general procedure described in Step 8 of Preparation 1-6 )- ton. 定_2·ylamine 157475.doc -130- 201211039 yl]-1-methyl-6-o-oxy-1,6-dioxa-pyridazin-3-yl}-2-hydroxyl Base-phenyl)_6_t-butyl-8-fluoro-2H-phthalazin-1-one. After treatment, it was re-expanded by dissolving with 3% methanol/dichloromethane, followed by 5 〇/〇methanol/diqi methane, 80/sterol/dichloromethane and 11% methanol/dichloromethane. The tannic acid preparation type TLC was carried out to purify the product. This gave the desired product (96 mg) as a pale brown powder. (M+H) = 654 m/e. iH NMR (3〇〇 mHz, chloroform δ ppm 1_21 (s,6 Η) 1.40 (s,9 H) 2 1]L (five peaks, j=7 20 ΗΖ, 2

(s, 2 Η) 6.90 (d, /=9.06 nz,! H) 7 29 (dd, J=8 88, 2 83 Hz, 1 H) 7.39-7.69 (m,5 H) 8.04 (d, /= 2.64 Hz, 1 H) 8.27 (d, •7=2.64 Hz, 1 H) 8.32 (s,i H) 8 51 (s,)H). Process C Preparation 1-14

Dibutyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(2- This example illustrates "6-third 157475.doc *131. 201211039 hydroxy-2-methyl- Propoxy)pyridin-2-ylamino]_1_fluorenyloxy-1,6-dihydro-pyridazin-3-yl}-styl)-2H-pyrazine-1-one synthesis. Step 1. Preparation of 1-(6-amino-pyridin-3-yloxy)-2-indolyl-propan-2-ol

Anhydrous dimercaptomethylhydrazine containing 6-aminopyridine-3-ol hydrobromide (700 mg, 3.66 mmol) and 1-oxa-2-mercapto-2-propanol (597 mg '5.5 mmol) A microwave flask of the amine (17 ml) solution was charged with cesium carbonate (3.7 g, 11 4 mmol) and the material was heated in a microwave oven at 140 ° C for 3 hours. The bottle was cooled to ambient temperature and the solvent was concentrated in a vacuum (rotary evaporator / mechanical polymerization). The residue was dissolved in dichloromethane and filtered under a full rinse with dichloromethane to remove insolubles. The crude material was purified by silica gel eluting with a gradient of 2% to 1% decyl alcohol / hexanes to give the desired product (449 mg) as a light-brown viscous oil. solidification. MS (H+) = 183 m/e. Step 2. Preparation of 6-gas-4-[5-(2-carbo-2-methyl-propoxy)-indenyl-2-aminoamine]-2-mercapto-2-indole-pyrazine_ 3_ketone 157475.doc •132· 201211039

ο

OH is prepared using the general procedure described in Step 6 of Preparations 1-6 (2-hydroxy-2-indenyl), and L. ) - Pyridyl 4-ylamino 3-ketone. The crude product was purified by preparative thin-layer chromatography (10) using 4.5% methanol / hexanes, &lt;RTI ID=0.0&gt; 392 mg).(M+H)+=325 m/e. Step 3. Preparation of 2-(6-t-butyl-8-fluorosideoxy-m-pyridazine_2_师6_ -2-mercapto-propoxy)-m-amino-amine] small methyl heptaoxy-1,6-dihydro-pyridazin-3-yl}-phenylmethyl ester

Under the conditions described in Step 7 similar to Examples 1-6, but using 6_gas_4_[5_(2_transyl-2-methyl-propoxy)_. ratio. Alkylamino]_2-methyl-2H-pyridazine-3-indole instead of 6-chloro-4-[5-(2-dimethylaminodimethyl-ethoxy)-pyridin-2- The aminoamino]-2-mercapto-2HH3 is used to carry out the reaction. After the treatment, the product was purified by preparative thin layer chromatography (2 157475.doc - 133 - 201211039 trays) by dissolving with 5% methanol / dichloromethane. This gave the desired product as a pale yellow powder (as well as some of the succinated product) (284 mg). (M+H)+=657 m/e. Example 14 Step 4. Preparation of 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(2-hydroxy-2-indolyl-propoxy)-°咬-2-ylamino]-1-indolyl-6-o-oxy-1,6-dihydro-oxo-3-yl}-phenyl)-2H-phthalazin-1-one

This reaction was carried out under conditions similar to those described in Step 8 of Example I-6. After the treatment, the product was purified by preparative thin layer chromatography (2 disks) by elution with 3.5% sterol/dichloropurine. The receiver was simmered with 5% methanol/two gas to re-expand the disk. This gave the desired product (195 mg) as a pale yellow solid. DMSO-c/6) δ ppm (M+H)+=615 m/e. 4 NMR (300 MHz, 1.16 (s, 6H) 1.37 (s, 9 Η) 3.72 (s, 2 Η) 3.76 (s, 3 Η) 4 32- 4.46 (m, 2 Η) 4.51-4.59 (m,1 Η) 4.61 (s,1 η) 7 39 (dd J-8.69, 3.02 Hz, 1 H) 7.43-7.57 (m, 4 H) 7.69-7.78 (m, 1 H) 7.86 (br. s,1 H) 8.02 (d, &lt;7=2.64 Hz, 1 h) 8.39 (s, 1 H) 8.50 (d, /=2.64 Hz, 1 H) 9.31 (s, 1 H).

Process D 157475.doc -134- 201211039

Preparation 1-15

Ο 0 Ο This example shows that "2-[8-fluoro-2-(2-hydroxyindolyl-3-{1-indolyl-5-[5-(norpoline-4 -methyl))-α ratio σ -2-ylamino]-6-tertiaryoxy-1,6-diaza-ruthenyl-3-methyl}-phenyl)-1-yloxy-1,2-dihydro-isoquinoline Synthesis of -6-yl]-2-mercapto-propionitrile. 157475.doc •135· 201211039 Step 1. Preparation of 2,4,6-trifluoro-N-(2-hydroxy-M-dimethyl-ethyl)-benzoate

A flask equipped with a vaporized calcium drying tube was fed with 2,4,6•trifluorobenzoic acid (25 g, 142 mmol), and dissolved in anhydrous dichloromethane (22 mL). The material was cooled to 0 ° C (ice bath) and ethylene oxalate (13.2 m 156 mmol) was added thereto via a syringe. Anhydrous dimethylformamide (104 mg, 1.42 mmol) was subsequently added and moderate bubbling was observed. After 15 minutes, the cooling bath was removed and the mixture was stirred vigorously for 5 hours. The volatiles were concentrated in vacuo (rotary evaporator) and the residue was dissolved in anhydrous dichloromethane (15) and cooled to 0 ° C (ice bath) and slowly added dropwise to the solution 2-Amino-2-methyl-1-propanol (27.2 w, 284 mm 〇1) was added. After the addition was completed, the cooling bath was removed and the mixture was allowed to warm to ambient temperature overnight. The reaction as described above was repeated on the same scale, and the combined reaction product was treated as follows: The heterogeneous mixture was suction-filtered under a rinse with dioxane (about 3 ml). The first filtrate was left in place and the solid was rinsed again with a second gas (500 ml) using slow gravity filtration. The dioxane in the second filtration was concentrated in vacuo to give a very pure product (2·9 g) as a crystalline solid. The methylene chloride solution in the first transition was concentrated in vacuo to give an impure brown residue. This material was dissolved in di-methane (2 〇〇 mi) and water (25 〇 mi) and oscillated in a separatory funnel. The organic phase was collected and the aqueous phase was back extracted with dichloromethane (2M 20 mL). The two gas methane phases were combined and dried (sulfate 157475.doc -136 - 201211039 town). Filtered and started in a vacuum A-L A + wet morning shrinkage. The crude residue was purified by trituration from auto-hydrogen methane/hexane to give the desired product (43.8 g) as a yellow solid. (M+H)+=246 m/e. Step 2. Preparation of 4,4-dimethyl-2-(2,4,6-trifluoro.phenyl)_4,5-diaza-d

By slowly adding '2,4,6-trifluoro-n-(2-hydroxy-1,1-dimethyl-ethyl)-benzoguanamine (43 8 g, 177" mm over 25 minutes 〇i) Thionine chloride (58 9 ml, 415 mmol) was added to a solution of anhydrous dichloromethane (400 mL) (the reaction flask was immersed in an ice bath to control the temperature in the middle of the addition). After the addition was completed, the material was stirred overnight at ambient temperature. The volume was reduced to 30% by concentration under vacuum. Ethyl (2 〇〇 ml) was added thereto and a solid precipitate (39.94 g of an off-white solid) was collected by filtration. The filtrate was kept in the filtrate and the solid matter was dissolved in water (12 ml) and treated with aqueous sodium hydroxide (2 N, 55 ml). Ethyl acetate (丨 2 〇 ml) was added, and the mixture was transferred to a separatory funnel and shaken. The organic phase was collected and washed with an equal volume of water. The ethyl acetate phase was collected and the aqueous phase was back extracted with ethyl acetate (2 x 100 mL). The combined organic phase was dried (MgSO4) EtOAcjjjjjjj (M+H)+=230 m/e. Step 3 · Preparation of 2-(2,4-fluoro-6-fluorenylphenyl)_4,4-dimethyl- 4,5-dihydro-σ oxa 0 157475.doc -137· 201211039

Methyl-2-(2,4,6-trifluorophenyl). 4,5-dihydropurine (16.8 g, 73.3 mmol) in anhydrous tetrazolium. Add a solution of methylmagnesium bromide (73 3 丨, ^ M in diethyl ether) to a solution of cooling (ice bath) in 15 Torr. The mixture was stirred at (TC for 2 hours, followed by (four) hours.

Warm up to ambient temperature. The reaction was carefully quenched by the addition of a saturated aqueous solution of ammonium chloride (3 〇M) and dissolved in water (2 〇〇ml) and ethyl acetate (15 〇ml), transferred to a separating funnel and collected organic phase. The organic phase was washed with water (2 mL) and EtOAc (EtOAc)EtOAc. The desired product is light yellow oil (16 31 g). (M+H)+= 226 m/e. Step 4. Preparation of 2-[4-(4,4-dimercapto-4,5-dihydro- Oxazol-2-yl)-3-fluoro-5-mercapto-phenyl]-2-methyl-propanenitrile

Under an argon atmosphere, it will contain 2·(2,4-difluoromethylphenyl)-4,4-dimercapto-4,5-dihydrooxazole 04.84 g, 65.9 mmol) and isobutyronitrile ( 9_11 g, 132 mmol) flask in a solution of anhydrous tetrahydrofuran (13 ° ^ 1) was cooled 157475.doc -138 - 201211039 to -15 ° C to -20 ° C (acetonitrile / dry ice bath). A solution of bis(trimethylsulfonylalkyl) potassium amide (171 ml, 0.5 Torr in benzene) was added via slow dropwise addition. The mixture was stirred at -15 ° C for 30 minutes, and then gradually heated to 15 ° C over about 1.5 hours. The material was quenched by the addition of a saturated aqueous solution of ammonium chloride (1 mL). Water (80 ml) and diethyl ether (50 ml) were added and the material was transferred to a sep. funnel and organic phase was collected. This material was washed with an equal volume of water and the organic phase was collected. The aqueous phase was back-extracted with diethyl ether (2×100 mL). By using 60. The product was purified by chromatography on silica gel eluting with EtOAc (EtOAc) elute This material is used "as is" in the subsequent steps. (M+H)+=275 m/e. Step 5. Preparation of 2-(4-(2-cyanopropyl-2-yl)_2-fluoro-6-nonylphenyl)_3,4,4trimethyl-4,5-dihydrooxazole_ 3_rust iodide

;1 〇刀钟, added by drop, to 2-[4-(4,4-dimethyl_4

g, purity 60% '52·2 mmol) Add deuterated methane (37 g, 261 mm〇i) to anhydrous acetonitrile (237 g of the solution. Transfer the mixture to heat to οι oil) and mix The flask was cooled to ambient temperature, then chilled in an ice-bath, and the precipitated solid product was collected by decansed to give the desired product (21.9 g) as a pale white solid. 157475.doc -139· 201211039 The substance was used "as is" in the next step. Step 6. Preparation of 4-(cyano-dimethyl-indenyl)_2-fluoro-6-methyl-benzoic acid

The flask was fed with 2-(4-(2-cyanopropyl-2-yl)-2-fluoro-6-methylphenyl)-3,4,4-trimethyl-4,5-di Hydrooxazole-3-rust iodide (21.9 g, 52.7 mmol) and decyl alcohol (89 ml). A solution of sodium hydroxide (1 〇 5 g, 263 mmol) in water (178 ml) was added to this syrup, and the material was heated in an oil bath at 8 〇t. The mixture was stirred vigorously for 60 minutes, followed by the addition of toluene (120 ml). The mixture was stirred in an oil bath and shaken for 5 minutes. Transfer the material to the separatory funnel and heat up the aqueous phase. This was acidified with 丨.5 N aqueous hydrochloric acid (to pH = 1). Ethyl acetate (25 ml) and water (5 mi) were added and the mixture was shaken in a sep. funnel. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate (2×4 〇m). The combined organics were dried with EtOAc EtOAc (EtOAc m. Cyano-dimethyl-methyl)-2~fluoroindolyl-benzamide

157475.doc •140 201211039 4-(2-Cyanopropan-2-yl)-2-fluoro-6-methylbenzoic acid (14 g, 35 mmol, purity 75%) was dissolved in anhydrous tetrahydrofuran (1 〇〇) To the melon, carbonyldiimidazole (11 2 g, "mmol") was added in four portions over a minute, and the mixture was stirred for 25 hours, followed by the addition of 28 〇/. Aqueous solution (2 〇. 4 ml). The mixture was stirred for 4 hr then concentrated under reduced pressure to remove 90% volatiles. The residue was dissolved in water (8 〇 〇) and dichloromethane (80 ml). The organic phase was collected and the aqueous phase was back-extracted with dichloromethane (3×60 ml). The combined organic phases were dried (MgSO4) filtered and concentrated in vacuo. The resulting semi-solid was purified by wet-purified hexanes / hexanes to afford the desired product (10.71 g &lt;RTI ID=0.0&gt; -(Cyano-dimethyl-indenyl VN-D-dimethylamino-methyl-(phantom-ylidene)_2-fluoro-6-methyl-benzamide

Will contain 4-(2-cyanopropan-2-yl)-2-fluoro-6-methylbenzamide (8.71 g, 31.6 mmol, purity 80%) and dimethylformamide dimethyl condensate Acetaldehyde (7.26 ml, 51.4 mmol) in tetrahydrofuran (61 ml) was placed in a 250 ml round bottom flask to give a non-smooth yellow suspension. The reaction mixture was heated to 63 ° C (oil bath) and stirred for 3 hours. The mixture was concentrated on a rotary evaporator and then dissolved in hexane (EtOAc). The mixture was stirred vigorously for several minutes until a white I57475.doc -141 - 201211039 precipitate formed. The product was collected by EtOAc (EtOAc) elute (m+H)+=276 m/e. Step 9. Preparation of 2-(8-fluoro-1-oxo-i,2-dihydroiso-isoquinolin-6-yl)_2-methyl-propanenitrile

4-(Cyano-dimercapto-indenyldidecylamino)-indenyl (E) subunit] 2-fluoro-6-mercapto-benzamide (1〇66 g, 38 7 mm 〇1) Dissolved in anhydrous tetrahydrofuran (100 ml), and placed in an oil bath heated to 55 lt. t. After 15 minutes, a solution of potassium tert-butoxide was added dropwise from the addition funnel (58 丨 丨, 丨M The reaction mixture was heated to 62 «&gt;c in THF and stirred for 2 hours. The resulting thick liquid was cooled to off temperature, and was taken dropwise with concentrated hydrochloric acid (5·3 ml). 〇ml), and the material was transferred to a separatory funnel to collect the organic phase and washed with a brine solution (25 ml). The aqueous phase was back-extracted with ethyl acetate (25 ml) and the organics were combined and dried over magnesium sulfate. Filtration and concentrating in the true </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;甲基基_Phenyl)·8_小小侧氧],2_Dihydroisoquinoline-6(yl)-2-fyl-propionitrile 157475.doc -142· 201211039

F F

2-(8-Fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)_2-methylpropionitrile (250 mg 'L09 mmol), 2,6-dibromobenzene A solution of formaldehyde (459 called i 74 mmol) and sodium bicarbonate (182 mg, 2.17 mm 〇1) in anhydrous disulfoxide (8 ml) was placed under vacuum and backfilled with argon (repeated twice more) ). Copper telluride (207 mg, 1.09 mm 〇i) was added to the material, and the flask was evacuated and backfilled with argon (repeated twice). The mixture was heated to an oil bath and stirred for 3.5 hours. The reaction mixture was cooled to ambient temperature and dissolved in ethyl acetate (40 ml) and water (40 ml). After thoroughly washing with ethyl acetate, the two-phase material was filtered through a plug of diatomaceous earth, and the filtrate and washing liquid were transferred to a separatory funnel, and the organic phase was collected. The material was washed with an equal volume of 5 Torr/0 brine solution and the ethyl acetate phase was collected. The aqueous phase was back extracted with ethyl acetate (2 x 30 ml). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by EtOAc (EtOAc) elute elute (M+H)+=413/415 m/e. Step 11. Preparation of 2-[8-fluoro-2-(2-carbamimid-3-{1·methyl-5-[5-(morpholin-4-carbonyl)-pyridin-2-ylamino] -6-o-oxy-1,6-dihydro-pyridazin-3-yl}-styl)-1-yloxy-1,2-dihydro-isoquinolin-6-yl]-2- Methyl-propionitrile 157475.doc -143- 201211039

6-Chloro-2-indolyl-4-(5-morphin-4-yl)indole sigma-2-ylamino)»达嗓_ 3(2H)-one (143 mg, 0.41 mm〇i ) 'bis (pinacoldyl) diboron (135 mg, 0.53 mmol), 2-dicyclohexylphosphino 2,, 4',6,_triisopropylbiphenyl (x-phos, 29 mg, 0.061 mmol) and potassium acetate (12 mg, i 23 mmol) were dissolved in dry dioxane (6.4 ml) and placed under vacuum and backfilled with argon (repeated five times). To this was added 1 bar of acetic acid (丨〇 mg, 〇 45 mmol), and the flask was evacuated and backfilled with argon (repeated five times). Heat the mixture to 10 (TC, and stir for 16 minutes in an oil bath. Cool the flask to ambient temperature' and filter the crude contents of the flask (via diatomaceous earth, rinse thoroughly with 3 ml of dioxane) to the second In a flask (immersed in a 丨丨〇〇c oil bath under an argon balloon), the second flask contains a vacuum degassing solution of the following reagent: 2_(2_(3_漠_2_ 曱 phenyl)-8- Said 1-o-oxy _i, 2-dihydroiso-quinone. Lin-based) _2_mercaptopropionitrile (169 mg, 0.41 mmol), potassium carbonate (283 mg, 2.04 mmol), tricyclohexylphosphine ( 35.1 mg, 〇_125 mmol) and bis(diphenylarhenylidene) palladium (3 5 mg '0.061 mmol) in n-butanol (〇.5 ml) 'dioxane (2.1 ml) and water (2 ml The mixture was stirred and heated for a few hours, then cooled to ambient temperature. The crude reaction mixture was filtered through a plug of chlorpyrifos with sufficient washing with ethyl acetate. Water was added to the combined filtrate and washings. 157475.doc -144- 201211039 (30 ml), and shake the material in a separatory funnel. The organic phase was collected and extracted with ethyl acetate (2×20 mL). The organic phase was combined with EtOAc (EtOAc m.) (Μ-Η)·=646 m/e. Example 15 Step 12. Preparation of 2-[8-fluoro-2_(2-hydroxyindole-3-{l-methyl-5-[5-(morpholine-) 4-carbonyl)-pyridin-2-ylamino]-6-sideoxy-1,6-diazino-3-yl}-phenyl)-1-yloxy-1,2-- Wind-iso-lin--6-yl]-2-methyl-c

Cooling 2-[8-fluoro-2-(2-indolyl-3-{l-methyl-5-[5-()--------------------- 2-Aminoamino]-6-tertiaryoxy-1,6-diaza-d-heptyl-3-yl}-phenyl)-1-yloxy-1,2-dihydro-isoquinoline- A solution of 6-yl]-2-methyl-propanenitrile (224 mg, 0.35 mmol) in methanol (2. A solution of sodium borohydride (65 mg, 1.7 mmol) in water (0. 75 ml) was added to this mixture by slowly dropwise. The mixture was stirred for 10 minutes and two additional sodium hydride (as described above) was added over 20 minutes. Carefully remove the upper aqueous phase from the two phase reaction solution. The sterol (1 ml) was added, and an aqueous solution of the sulphate (as described above) was added three more times over a period of about 25 minutes under 157475.doc • 145·201211039. Water (60 ml) and di-methane (6 〇 (6)) were added and the material was transferred to a separatory funnel and the organic phase was collected. The material was washed with an equal volume of 5 % by volume of a dilute brine solution and the two gas phase was collected. The aqueous phase was back extracted with two gas (2 x 40 ml). The combined organics were dried with MgSO4, filtered andEtOAc. Purification of the residue by EtOAc (1% to EtOAc) eluted eluted eluted eluted eluted elute Product (120 mg). (M+H)+=650 m/e. NMR (300 MHz, gas-J) δ ppm 1.81 (s, 6 Η) 3.53-3.81 (m, 8 Η) 3.83-3.91 (m, 1 Η) 3.92 (s, 3 Η) 4.26-4.45 (m, 2 Η) 6.62 (dd, J=7.55, 1.89 Hz, 1 H) 7.00 (d, J=8.31 Hz, 1 H) 7.22 (dd5 J=12.46, 1.89 Hz, 1 H) 7.33 (d, /=7.18 Hz , 1 H) 7.42 (dd, 7=7.93, 1.51 Hz, 1 H) 7.53 (d, /=1.89 Hz, 1 H) 7.57 (t, J=7.93 Hz, 1 H) 7.65-7.70 (m, 1 H 7.78 (dd, /=8.69, 2.27 Hz, 1 H) 8.41-8.47 (m, 2 H) 8.70 (s, 1 H).

Process E Preparation 1-16 157475.doc 146· 201211039

This example illustrates "6-t-butyl-8-fluoro-2-(3-{5-[5-((8)-2-hydroxy-3-indolyloxy-propoxy)-)-pyridyl- Synthesis of 2-aminoaminoindenyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxyindolyl-phenyl)·2Η-pyridazin-1-one . Step 1. Preparation of 2-gas-5-((S)-l-oxiranylmethoxy)-tonidine

In a 250 mL round bottom flask, 6-chloropyridin-3-ol (2.116 g, 16.3 mmol), triphenylphosphine (5.14 g, 19.6 mmol) and (R)-oxirane-2-ylmethanol (1.21 g' 1.08 ml, 16.3 mmol) was combined with THF (75.0 ml). Cool to 〇. (: Add DEAD (3.41 g, 3.1 ml ' 19.6 mmol). Brn the reaction mixture to 25 ° C and stir for 30 hours. Concentrate the reaction mixture in vacuo. by flash chromatography (8 g, 25 g) The crude product was purified by flash chromatography (4 g, 4% EtOAc EtOAc EtOAc) Product (1.8 g, 59%). (M+H)+ = 186 m/e. Step 2. Preparation of (S)-1-(6-gaspyridin-3-yloxy)-3-decyloxy -propan-2-ol

In a 125 mL round bottom flask, (S)-2-Ga-5-(oxiran-2-yloximeoxy)° was bitten (1.8 g, 9.7 mmol) in combination with MeOH (5.88 ml). A colorless solution was obtained. Cool to 0 °C. Add boron trifluoride etherate (138 mg, 123 μΐ, 970 μιηοΐ). Warm to room temperature. The reaction mixture was stirred overnight at room temperature. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut (M+H)+=218 m/e. Step 3. Preparation of 5-[(S)-2-(t-butyl-diindenyl-xanthoxy)-3-methoxy-propoxy]-. Bis-2-ylamine

(S)-1-(6-chloropyridin-3-yloxy)-3-decyloxypropan-2-ol (1.37 g 157475.doc -148· 201211039 6.29 mmol) and imidazole (857 mg, 12.6 Methyl) was combined in DMF (20 ml). DMAP (115 mg, 944 μπιοί) and TBDMS-C1 (1.23 g ' 8.18 mmol) were added in that order. The reaction was stirred at 25 ° C overnight. The reaction mixture was poured into 150 mL of H20 and evaporated over Et. The organic extract was washed with brine, dried over MgSO4 and evaporated. Purification of the crude material by flash chromatography (EtOAc, 40 g, EtOAc to 15% EtOAc hexanes) to yield 1.81 g of (S)-5-(2-(t-butyl decyl decyloxy) _3_Methoxypropoxy)-2-chloropyridine (5.4 mmol) was dissolved in 14 mL of THF in a sealed tube. 2-(Dicyclohexylphosphino)biphenyl (380 mg, 1.08 mmol) was added thereto to give a pale yellow solution. This solution was degassed with argon. Parathium (diphenylmethyleneacetone) dipalladium (0) (497 mg, 542 μηηοΐ), LiHMDS (16.3 ml of 1 M solution in THF, 16.3 mm 〇l) was added in that order. The reaction was placed under an argon atmosphere and sealed. The reaction mixture was heated to 90 ° C and stirred for 15 hours. The reaction was completed by LCMS. The mixture was cooled and diluted with EtOAc. The reaction mixture was poured into 15 mL of saturated EtOAc EtOAc (EtOAc). The organic layer was dried over EtOAc and concentrated in vacuo. The crude material was purified by EtOAc (EtOAc) elute (m+H)+=313 m/e. Step 4. Preparation of 4-{5-[(s)-2-(t-butyl-dimethyl-decyloxy)_3_methoxy-propoxy]-pyridin-2-ylamino}- 6-Gas-2-mercapto-2H-pyridazin-3-one 157475.doc •149· 201211039

In a 50 mL round bottom flask, (S)-5-(2-(t-butyldimethylmethylalkoxy)-3-methoxypropoxy)-indenyl-2-amine (340) Mg, 1.09 mmol), 4-di-6-gas-2-indole. Qin-3(2H)-net (292 mg, 1.31 mmol) and cesium carbonate (1.06 g, 3.26 mmol) were combined in dioxane (25 ml) to give an orange suspension. 4,5-bis(diphenylphosphino)-9,9-diindenyldiphenyl is added in sequence. South (94.4 mg, 163 μηιοί), ginseng (diphenylarbenium acetonide), two (0) (49.8 mg ‘ 54.4 μπιοί). The reaction solution was degassed with argon for 10 minutes and warmed at 95-105 ° C for 48 hours. The resulting reaction mixture was diluted with 200 ml of DCM. Add MgS04. The suspension was filtered and washed several times with DCM. The combined filtrate and washings were concentrated in vacuo. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut (M+H)+=455 m/e. Step 5. Preparation of 6-t-butyl-2-[3-(5-{5-[(S)_2-(t-butyl-didecyl-decyloxy)-3-methoxy-propane Oxy]pyridin-2-ylaminodipyridyl-methyl_6_sideoxy-1,6-dihydro-s--3-yl)-2-methylphenyl]_8_fluoro_ 2Η-β too nois-1-one 157475.doc •150· 201211039

In a 50 mL tube, (5)·4-(5_(2_(t-butyldimethylmethylalkoxy)-3-methoxypropoxy)D is more than a 2-amino group) 6-Chloro-2-methylindole. Qin _

3(2H)-ketone (178 mg, 391 μηιοί) and 2-(6-t-butyl-8-fluoro-i_ oxo-oxazine-2(1Η)-yl)-6-(4,4) , 5,5-tetramethyldiboron-flavored benzoate (332 mg, 469 μιηοΐ) was combined in n-butanol (4 ml) to give an orange solution "add 1 mL of water with argon The gas is purged of the reaction mixture. X-PHOS (18_6 mg, 39.1 μιηοΐ) and tripotassium phosphate (166 mg, 782 μηιοί) were added. After bubbling argon through the reaction mixture for 5 minutes, bis(diphenylarbeniumacetone)-pound (0) (11.2 mg, 19.6 μηιοί) was added. The resulting suspension was heated in an oil bath at ll 〇 ° c for 1.5 hours. (S)-4-(5-(2-(2-butylmethylsulfanyloxy)-3-methoxypropoxy)-π-bito-2-amino)- There is no residue of 6-chloro-2-mercaptopyridin-3 (2Η)-one. Two major products were observed by LCMS: the acetamidine product and the deacetylated product. The reaction mixture was allowed to cool to 25 ° C overnight. The reaction mixture was concentrated to a small volume, poured over EtOAc EtOAc (EtOAc) The organic layer was dried with EtOAc (EtOAc m. These products were combined and concentrated to give a 1:1 mixture of 290 mg of the succinated product and the product of decyl 157475.doc - 151 - 201211039. This mixture was dissolved in 15 mL THF and treated with 2 mL 1 N NaOH. The reaction mixture was heated to 60 ° C and stirred for 20 hours. The reaction was mostly completed by UC analysis. The reaction mixture was poured into 100 mL of H.sub.2 and extracted with EtOAc (3.times.50 mL). The combined organic extracts were washed with brine, dried over EtOAc EtOAc The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut (M+H)+=745 m/e. Example 16 Step 6. Preparation of 6-t-butyl _8_fluoro-2_(3-{5_[5_((s)_2_hydroxy_3_methoxy-propoxy)-° ratio -2- Aminoamino]-1-indolyl-6-yloxy-1,6-dihydro-d--3-yl}-2-carboxyl-phenyl)_2Η-α大嘻-1-one

In a 100 mL round bottom flask, (8)-6-t-butyl-2-(3-(5-(5-(2-(2-butylmethyl))-indole Oxypropoxyl ratio D to 2 _ ylamino)-1-indolyl-6-o-oxy-1,6-dihydropyridazin-3-yl)-2-(hydroxyindenyl) -8-fluoropyridazine-1(2Η)-one (214 mg, 287 μπιοί, 1.00 eq.) was combined with THF (6.0 ml) to give a yellow solution. Add TBAF (500 μM 1 μ 157475.doc -152 - 201211039) The solution in THF, 500 μηιοί), and the loss at 25 ° C!: The resulting solution was mixed for 1 hour. The reaction was completed by LCMS. The reaction mixture was poured into 75 mL of H20 and EtOAc (l &gt;&lt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ br> The crude material was purified by chromatography (EtOAc EtOAcjjjjjjjjj The mixture was triturated with diethyl ether. The obtained white solid was washed with diethyl ether/hexane to afford 11 2 mg of pure product in the form of a white powder. (M+H)+= 631 m/e. Towel NMR (300 MHz, gas j) δ ppm 1.44 (s, 9 Η) 3.44 (s, 3 Η) 3.53- 3.64 (m, 2 Η) 3.91 (s,3 Η) 4.03-4.11 (m,2 Η) 4.13-4.22 (m,1 Η) 4.42 (s,2 Η) 6.98 (d, J=8.69 Hz, 1 H ) 7.28-7.35 (m, 1 H) 7.43-7.62 (m, 4 H) 7.64-7.69 (m, 1 H) 8.06 (d, /=3.02 Hz, 1 H) 8.27-8.32 (m, 2 H) 8.48 (s, 1 H) Example 17 Preparation of 6-t-butyl-8-fluoro-2-(3-{5-[5-((R)-2-hydroxy-3-methoxy-propoxy) )-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-indenyl}-2-hydroxymethyl-phenyl)-2indole-pyridazine-1- Ketone 157475.doc -153- 201211039

Prepared by a procedure similar to that of Example 16 except that (S)-oxiran-2-ylmethanol was used instead of (R)-oxiran-2-ylmethanol in Step 1, to give a white powder. Product (107 mg). (M+H)+=631 m/e. NMR (400 MHz, chloroform 4) 3?卩1111.44(8,9 1'1)3.44(3,:3 11)3.53-3.63 (m,2 Η) 3.91 (s, 3 Η) 4.02-4.12 (m, 2 Η) 4.14-4.22 (m, 1 Η) 4.42 (s, 2 Η) 6.99 (d, J=8.78 Hz, 1 H) 7.32 (dd, /=9.03, 3.01 Hz, 1 H) 7.45-7.61 (m , 4 H) 7.64-7.69 (m, 1 H) 8.06 (d, /=2.76 Hz, 1 H) 8.29 (d, /=2.51 Hz, 1 H) 8.32 (s, 1 H) 8.47 (s, 1 H )

Process F Preparation 1-18 157475.doc -154· 201211039

This example illustrates "6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{l-fluorenyl-5-[5-((S)-l-fluorenyl- fluorenidine) -2-yl)-n-pyridin-2-ylamino]-6-sideoxy-1,6-dihydro-pyridazin-3-yl}-phenyl)-2indole-pyridazin-1-one The synthesis. Step 1. Preparation of 2-chloro-5-((S)-l-methyl-n to 0 each bit-2-yl)_α ratio. set

A 100 mL RB flask was placed under an argon atmosphere and vacuum degassed with argon. Solvent (hexane (4 ml) and methyl stupid (12 mi)) were added to the flask. Add N,N-dimethylethanolamine (1.07 g, 1 > 21 (6), 12 〇 on call. Cool the reaction mixture to o ° C. Add n-butyl lithium (8 66 ml, 2 5 M, in hexane) (The mixture was stirred for 3 minutes. TC. cold-methylpyrrole. 1,4-yl) pyridine was stirred at -20 ° C. The reaction mixture was mixed to -20 ° C. Add bite (650 mg, 0.64 ml) , 4.01 mmol) 〇 157475.doc • 155-201211039 Compound for 1 hour. The reaction mixture was cooled to -78 ° C, and hexane (8 ml) containing hexaethane (3.8 g '16.0 mmol) was added. The reaction mixture was stirred for 1 h at 78 ° C. The reaction was quenched with EtOAc EtOAc EtOAc. The reaction mixture was poured into 5 mL of H20 and extracted with DCM (3.times.25 mL). The organic layer was dried over Na2S04 and concentrated in vacuo. The crude material was purified to give the desired product (467 mg, 59%). 4 NMR (300 MHz, chloroform-d) δ ppm 1.56-2.05 (m, 3 H) 2.16-2.40 (multiple peaks and overlaps) Single peak, 5 Η) 3.09 (t, J=8.31 Hz, 1 Η) 3.17-3.29 (m, 1 Η) 7.23-7.32 (m, 1 Η) 7.68 (dd, 7=8.12, 2.45 Hz, 1 H) 8.30 (d, J = 2.27 Hz, 1 H) Step 2. Preparation of 5-((S)-l-methyl-pyrrolidinyl-2-yl)-pyridine-2-amine

'(s)-2-Ga-5-(1-methylpyrrolidin-2-yl)pyridine (622 mg, 3.16 mmol) and 2-(dicyclohexylphosphino)biphenyl in a 75 mL sealed tube (222 mg, 633 μηιοί) combined with THF (15 ml) gave a pale yellow solution. The solution was degassed with argon. Add gin (diphenylmethyleneacetone) dipalladium (〇) (29 〇 mg, 316 μηιοί). LiHMDS (9.49 ml of a solution of hydrazine in THF, 9.49 157475.doc -156.201211039 mmol) was added. The reaction was placed under an argon atmosphere and sealed. The reaction mixture was heated to 90 ° C and stirred for 15 hours. The reaction was completed by tic analysis. The reaction mixture was cooled to room temperature and diluted with EtOAc. The reaction mixture was poured into EtOAc (4×75 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (40 g, 1 〇〇 / 0 to 50% (60:10:1 CH2C12: methanol: NH4OH) / HaCh gradient) with a step gradient to give the desired product (560) Mg, 99%). 4 NMR (300 MHz, chloroform δ ppm 1.57-2.03 (m, 3 H) 2.04-2.39 (multiple peaks and overlapping singlet, 5 η) 2.92 (t, "7=8.12 Hz, 1 Η) 3.14-3.29 (m , 1 Η) 4.40 (br. s., 2 H) 6.51 (d, /=8.69 Hz, 1 H) 7.47 (dd, /=8.31, 2.27 Hz, 1 H) 7.95 (d, 7=2.27 Hz, 1 H) Step 3. Preparation of 6-chloro-2-indolyl-4-[5-((S)-l-methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-2H-indole嗓-3-_

In a 50 mL round bottom flask, 5-((S)-l-indolyl-pyrrolidin-2-yl)-pyridin-2-ylamine (560 mg ' 3.16 mmol), 4-bromo-6- gas 2-Methylpyridazin-3(2H)-one (847 mg, 3.79 mmol) and carbonitrile (3.09 g, 9.48 mmol) were combined with dioxane (25 ml) to give an orange suspension. Add 157475.doc •157- 201211039 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (274 mg, 474 μιηοΐ, 0.15 equivalent), ginseng (diphenyl) Methylene acetonide) dipalladium (〇) (145 mg, 158 μηιοί, 0.05 eq.). The reaction was degassed with Ar for 1 min and heated at 95-105 °C for 4 h. There is no residue in aniline SM. The reaction mixture was diluted with 200 ml of DCM. Add MgSCU and stir. The reaction was filtered and the filter cake was washed several times with DCM. The combined filtrate and washings were concentrated in vacuo. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut (M+H)+=320 m/e 〇Example 18 Step 4. Preparation of 6-t-butyl-8-fluoro-2-(2-hydroxydecylmethyl_5_[5-((S)-l) -mercapto-n-pyrrolidin-2-yl)-pyridin-2-ylamino]-6-sideoxy],6-dihydro-d.qin-3-yl}-phenyl)-2Η-β Too -1-_

(S)-6-Ga-2-methyl-4_(5-(1-decylpyrrolidin-2-yl)pyridin-2-ylamino)pyridazine_3 in a 5〇mL RB flask (2H)-ketone (125 mg, 0.39 mmol) and 2-(6-t-butyl-8-fluoro-1-oxo-oxazine-2 (ie, _yl)_ 6-(4,4, 5,5-Tetradecyl-1,3,2-dioxaboron-2-yl)benzyl ester (331 mg, 468 μιηοΐ) was combined with BuOH (4 ml) to give an orange solution. Add i mL 157475. Doc -158· 201211039 Water. Purified with argon. Add X-PHOS (18.6 mg, 39.0 μηι〇1) and tripotassium phosphate (106 mg, 78 〇μιηοΐ), and argon gas was bubbled through for 1 Torr. Add bis(dibenzylideneacetone)-i 2 mg, 195 μηιοί). The resulting reaction mixture was purged with argon and warmed in an oil bath for 1.5 hours under n. Two major products, the B-stuffed product and the deacetylated product, were observed by LCMS. The reaction was allowed to cool to room temperature overnight and then concentrated to a small volume. The reaction mixture was poured into EtOAc (3×75 mL). The organic layer was washed with brine and dried over EtOAc EtOAc. The crude material was purified by flash chromatography (24 g, DCM with 1% to 5% MeOH) to give two peaks. The two peaks were combined and concentrated to give a mixture of 23 8 mg of the acetylated product and the hydrazine-based product i: hydrazine. This mixture was dissolved in 15 mL THF and treated with 2 mL 1 N NaOH. The reaction mixture was heated to 60 ° C and allowed to mix for 25 hours. The reaction was nearly completed by tic analysis. The reaction mixture was poured with EtOAc (2×50 mL)EtOAc. No product remains in the aqueous phase. The combined organic extracts were washed with brine, dried over EtOAc EtOAc The crude material was purified by flash chromatography (EtOAc, EtOAc (EtOAc:EtOAc) (M+H)+=610 m/e. Example 19 Preparation of 6-t-butyl-8-gas-2-(2-purinyl-3-{l-fluorenyl-5-[5-((R)-l-methyl-pyrrolidin-2- ))-pyridin-2-ylamino]-6-o-oxy-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one I57475.doc •159 · 201211039

Prepared by a procedure similar to that of Example 18, but substituting (R)-3-(l-methylpyrrolidin-2-yl)pyridine for (S)_3_(1-methylpyrrolidin-2-yl in Step 1 Pyridine gave the desired product (78 mg) as a white powder. (M+H)+=610 m/e. Preparation 1-20 Step 1. Preparation of 6-azido-N,N-dimercapto-nicotinamide

€ N

In a 500 mL round bottom flask, 6-chloro-N,N-dimethylnicotinamide (8.15 g '44.1 mmol) was combined with DMF (50.0 ml) to give a brown solution. Agglomerated sodium (3.44 g, 53.0 mmol) was added, and the reaction mixture was heated to 120 ° C and stirred for 60 hours. The reaction mixture was diluted with EtOAc (EtOAc (EtOAc) The organic layer was combined, washed with EtOAc EtOAc EtOAc EtOAc MeOH was added and the whole mixture was 157475.doc -160 201211039 a solidified upon shaking. Under vacuum, &amp;L&amp;^# has two distilled crude products overnight. The pasty solid was recrystallized from EtOAc/Hex. Speaking

The solid was filtered through Ba and washed with a minimum of hexane. The white powder was dried under vacuum for 3 hours to give 2.23 g of the title compound. lH NMR (3〇〇黯, chloroform_d) 8% (s, 1H), 8.09 (d, J=9.1 Hz, 1H), 7.75 (dd, J=9.1, 1.5 Hz, 1H), 3.15 (br· s., 6H). Step 2. Preparation of 6-amino-N,N-dimercapto-nicotinamide

In a 250 mL round bottom flask, 6-azido-n,N-diindenyl nicotinamide (2.26 g, 11.8 mmol) was combined with ethyl acetate (5 mL) and methanol (30 mL). A yellow solution was obtained. 10% Pd/C (200 mg, 1.88 mmol) was added and the reaction mixture was taken and filled twice with 1 . The reaction mixture was stirred at 25 ° C under a H 2 balloon pressure for 17 hours. The reaction mixture was filtered through celite and washed with MeOH. The filtrate was concentrated in vacuo and dried <RTI ID=0.0> (M+H)+=166 m/e. 4 NMR (300 MHz, chloroform-d) δ: 8.21 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 8.3, 2.3 Hz, 1H), 6.50 (d, J = 8.7 Hz, 1H), 4.69 (br. s., 2H), 3.08 (s, 6H). Step 3. Preparation of 2-(6-t-butyl-8-say-1-oxooxy-1H-.tano-2-yl)-6-157475.doc • 161 - 201211039 [5-(5) - dimethylamine-mercapto-pyridin-2-ylamino)-indole_methyl_6_sideoxy-1,6-dihydropyridazin-3-yl]-phenylmethyl ester

In a 250 mL round bottom flask, 6_(6_gas_2_mercapto_3_sideoxy-2,3-dihydropyridazin-4-ylamino)-N,N-dimethylnicotine Indoleamine (ion g, 3.42 mmol), 2-(6-t-butylfluoro-1-one oxime oxime (ih)-yl)-6-(4,4,5,5-four Methyl-1,3,2-dioxaboron-2-ylbenzoyl ester (2.2 g, 4.45 mmol) and Cs2C03 (3.34 g' 10.3 mmol) and two "smoke (20 ml) and water (2.00) M) Combine to give a dark brown suspension "purify the suspension with argon and add PdCl2 (DPPF) (83.8 mg, 103 μιηοΐ). The reaction mixture was heated to 85 ° C' and stirred for 3 hours. Cool to 25. (: and diluted with DCM. Add NaaSO4 and filter the mixture with diatomaceous earth. Wash the filter cake with dcm until clarified and concentrate the brown filtrate in vacuo. by flash chromatography (200 g, 〇% to 5) The crude material was purified by EtOAc EtOAc EtOAc. (M+H) = 640 m/e ° Example 20 Step 4. Preparation 6-{6-[3-(6-Tert-butyl-8-fluoro-indole·sideoxy·1Η_pyridazine_2_ Base)_2_ 157475.doc •162- 201211039 via methyl-benzyl]-2-mercapto-3-sideoxy-2,3-diqijianuqin_4_ylamino}_ N,N- Dimercapto-nicotinamide

In a 500 mL round bottom flask, '2-(6-t-butyl_8-fluoro-indole-oxo-oxazine-2(1H)-yl)-6-(5-(5-(two) Methylamine decylpyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydroindole "Qin-3-yl)benzyl ester (1142 g, 1.79 mmol) Combine with dioxane (25 ml) and 1 M LiOH (10 ml) to give a pale yellow suspension. The reaction mixture was stirred at 25 ° C for 17 hours. The crude reaction mixture was concentrated in vacuo. Between the water and the water, the emulsion was obtained and the aqueous layer was extracted with DCM. The organic layer was dried over Na.sub.2SO.sub.sub.sub.sub.sub.sub. The title compound was obtained as a white solid. (M+H)+= 598 m/e. 丨11 NMR (300 MHz, wind imitation - ί/) δ: 8.68 (s, 1H) , 8.46 (d, J = 2.6 Hz, 2H), 8.29 (d, J = 2.6 Hz, 1H), 7.79 (dd, J = 8.3, 2.3 Hz, 1H), 7.64 - 7.69 (m, 1H), 7.53- 7.63 (m, 3H), 7.50 (t, J=2.1 Hz, 1H), 7.47 (d, J-1.5 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 4.43 (s, 2H), 3.92 (s, 3H), 3_11 (s, 6H), 1.43 (s, 9H) Preparation 1-21 Step 1. 157475.doc 201211039 Preparation 6-Chloro- 4- [5-(4-starting-4-mercapto-π-D-l-dec-1-yl)-α ratio π--2 -ylamino]-2-indolyl-2-indole-3-one

In a 250 mL round bottom flask, 6-(6-Gas-2-mercapto-3-oxo-2,3-dihydroindole-Qin-4-ylamino) was acid tested (195 mg, 695 μιηοΐ), 4-mercapto-4-acetate (80.0 mg, 695 μηιοί), HOBT (138 mg, 903 μπιοί) and Hugh's test (269 mg, 364 μΐ, 2.08 mmol) with DMF (13 ml) ) Combine to give a light yellow suspension. EDC (173 mg, 903 μιηοΐ) was added, and the reaction mixture was heated to 10 ° C and stirred for 24 hours. Further, 4-indolyl base sigma-4-ol (8Q.0 mg, 695 μιηοΐ), HOBT (106 mg, 695 μιηοΐ) and EDC (133 mg, 695 μηιοί) and 2 ml of DMF were added. The reaction mixture was heated to 10 ° C and stirred for 24 hours. The reaction was cooled to 25 &lt;0&gt;C and quenched with water. The aqueous layer was back extracted with EtOAc (3×75 mL). The combined organic layers were washed with EtOAc EtOAc EtOAc EtOAc The residue was dissolved in DCM / MeOH (9: 1) and filtered. The filtrate was concentrated in vacuo to give a pale yellow solid. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut elut (M+H)+=378/38〇Step 2. 157475.doc -164- 201211039 Preparation of 2-(6-t-butyl-8-fluoro-1-indolyl-ΐΗ-αΑσ秦-2 - -6-{5-[5-(4-Hydroxy-4-indolyl-piperidin-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-oxirane-1 ,6-dihydro-pyridazin-3-yl}-phenylmethyl ester

ΟGuang added 6-chloro-4-(5-(4-hydroxy-4-methylpiperidin-1_yl)0-indol-2-ylamino)-2-indole to a 10 mL microwave vial Ji Jian. Qin-3(2H)-ketone (33 mg, 87.3 μιηοΐ), 2-(6-t-butyl-8-fluoro-1-oxo-oxetazine-2(1H)-yl)-6-( 4,4,5,5-tetradecyl-1,3,2-dioxaboromid-2-yl) benzyl ester (56.1 mg, 114 μιηοΐ) and Cs2C03 (99.6 mg, 306 μπιοί). Caustic (5 ml) and water (0.5 ml). The yellow suspension was purged with argon and PdCh(DPPF) (7·13 mg, 8.73 μιηοΐ) was added. The bottle was capped and heated in a microwave at 125 °C for 30 minutes. The reaction was cooled to 25 ° C and diluted with DCM. Na; 2S 〇 4 was added, and the mixture was filtered through Shixia. The filter cake was washed with DCM to EtOAc. (M-H)+=708 m/e. Example 21 Step 3. Preparation of 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-4-indolyl-piperidine-1-carbonyl) -pyridin-2-ylamino]methyl_6_sideoxy_丨,6_dihydro_157475.doc -165- 201211039 叫致-3-基}-phenyl)-2H-°太嘻- 1-ketone

In a 250 mL round bottom flask, 2-(6-t-butyl-8-fluoro-1-o-oxo-oxazine-2(1H)-yl)-6-(5-(5-(4) -hydroxy-4-mercaptopiperidinyl-1 carbonyl) ° 定-2-ylamino)-1-indolyl-sideoxy-i,6-dihydromethane -3-yl) benzoyl The ester (62 mg, 87.4 μιηοΐ) was combined with dioxane (5 ml) and 1 M LiOH (1 ml) to give a brown solution. The reaction mixture was stirred at 25 ° C for 5 hours. The crude reaction mixture was concentrated in vacuo and partitioned between DCM and water. The aqueous layer was back extracted with DCM (2 x 25 mL). The combined organic layers were washed with EtOAc EtOAc (EtOAc) The crude material was purified by flash chromatography (EtOAc EtOAc EtOAc EtOAc) The material was re-purified by flash chromatography eluting elut elut elut elut elut elut elut (M+H)+=668 m/e. NMR (300 MHz, chloroform-d) δ: 8.69 (s, 1 Η), 8.39-8.47 (m, 2H), 8.29 (d, J=2.3 Hz, 1H), 7.75 (dd5 J=8.5, 2.1 Hz, 1H ), 7.43-7.70 (m, 5H), 6.99 (d, J=8.7 Hz, 1H), 4.43 (br. s.5 2H), 3.91 (s, 3H), 3.20-3.87 (m, 4H), 1.65 (br. s·, 6H) 1.43 (s, 9H). 157475.doc -166- 201211039 Preparation 1-22 Step 1. Preparation of 6-(6-tridentyl. 1,4--3-yl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid Tributyl ester

Ο

I 〇 In a 25 mL pear-shaped flask, 2,6-diazaspiro[3.3] Gengyuan_2-carboxylic acid, third brewing (2_81 g, 14.2 mmol), 5-oxadistone. The combination of deciduous (2.88 g, 14.2 mmol) and hydrazine (1.58 g, 2.17 ml. 15.6 mmol) with DMSO (12 ml) gave a pale yellow solution. The reaction mixture was heated to 90 ° C and stirred for 40 hours. It was cooled to 25 &lt;0&gt;C and the reaction mixture was diluted with EtOAc EtOAc (EtOAc &lt; The combined organic layers were washed with brine (1×50 mL), dried over Na. The purple oil was used in the crude material as a subsequent reduction. (m+h)+= 321 m/e. Step 2. Preparation of 6-(6-amino-pyridyl-3-yl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester 157475.doc 167· 201211039 in 500 mL In a pear-shaped flask, 6-(6-cartopyranol ratio -3-yl)-2,6-diazaspiro[3.3]heptane-2-furoic acid tert-butyl ester (4.54 g, 14 • 2 mm 〇l) and 10% Pd/C (662 mg, 6.22 mmol) in combination with ethyl acetate (150 ml) and decyl alcohol (50 ml). The mixture was evacuated and filled twice with H2, then stirred at 25 ° C under H2 balloon pressure overnight. The mixture was filtered through celite and the filter cake was washed with MeOH. The filtrate was concentrated in vacuo to give a purple oily solid. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut (M+H)+=29 1 m/e. Step 3. Preparation of 6-[6-(6-Gas-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-. 0-0-3-yl]-2,6-diazai-hetero-spiro[3.3]heptan-2-indole tridecyl

157475.doc • 168 - 201211039 In a 250 mL round bottom flask, 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tertidine Vinegar (870 mg, 3.00 mmol), 4-di-6-chloro-2-methylpyridazine-3(2H)- _ (670 mg, 3.00 mmol), xantphos (260 mg, 449 μιηοΐ), Cs2C03 (2.93 g, 8.99 mmol) and Pd2(dba)3 (137 mg, 150 μιηοΐ) combined with dioxane (25.0 ml) gave a dark brown solution. The reaction mixture was heated to 1 ° C under argon and stirred for 20 hours. The reaction was cooled to 25. (:, diluted with DCM, and NadO4 was added. The mixture was filtered over a pad of Celite, and the filter cake was washed with DCM, and the filtrate was concentrated in vacuo to give a dark brown semi-solid. by flash chromatography. The crude material was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) (M+H)+=433/435 m/e. NMR (300 MHz, chloroform-(1)5: 8.12 (s, 1H), 8.08 (s, 1H), 7.65 (s, 1H) ), 6.82 (d, J=l.5 Hz' 2H), 4_12 (s, 4H), 4.01 (s, 3H), 3.80 (s, 4H), ms (s, 9H). Step 4. Preparation 6- (6-{6-[2-Ethyloxyindolyl-3·(6_t-butyl_8_fluoro-丨_sideoxy-1H-blown Qin-2-yl)-phenyl] -2 - Mercapto-3-yloxy-2,3-dihydropyridazine-4-ylamino}-pyridin-3-yl)-2,6-diaza-spiro[3·3]g Alkano 2_decanoic acid third butyl 157475.doc 201211039

6-(6-(6-Gas-2-indolyl-3-oxo-2,3-diazapyridazin-4-ylamino)pyridin-3-yl in a 250 mL round bottom flask 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (300 mg, 693 μιηοΐ), acetic acid 2-(6_t-butyl-8-fluoro-1-side oxygen Pyridazine-2(1Η)-yl)-6-(4,4,5,5-tetradecyl-l,3,2-dioxocono o-on-2-yl)phenylhydrazine vinegar (445 mg, 901 μmol) And Cs2CO3 (677 mg, 2.08 mmol) in combination with dioxane (20 ml) and water (2.00 ml) gave a yellow suspension. The flask was evacuated and filled with argon, and PdCI2 (DPPF) (17.0 mg, 20.8 μιηοΐ) was added. The reaction mixture was heated to 85 ° C and stirred under argon for 3 hours. Further, PdCl 2 (DPPF) (17 mg, 20.8 μηηοΐ) was added, and the reaction mixture was heated to 85 ° C and mixed for 60 hours. Cool to 25 ° C and dilute with DCM. The reaction mixture was filtered through celite, and the filtrate was dried over Naz. The crude reaction mixture was concentrated in vacuo. The brown solid was used as a crude material in the subsequent reaction. (M+H)+=765 m/e. Step 5 - Preparation of 6-(6-{6-[3-(6-t-butyl-8-fluoro-1-oxo-1H-pyridazin-2-yl)-2-sulfonyl-benzene ]]-2-mercapto-3-yloxy-2,3-dihydroindole. Qin-4-ylamino}-pyridin-3-yl)-2,6-diaza-spiro[3.3] Heptane-2-decanoic acid tert-butyl ester I57475.doc .170- 201211039

In a 250 mL round bottom flask, 6-(6-(6-(2-(ethyloxymethyl)) 3-(6-tert-butyl-8-fluoro-1-yloxypyridazine- 2(1H)-yl)phenyl)_2.methyl-3-oxo-2,3-dihydropyridazin-4-ylamino).pyridin-3-yl)-2,6-di Azaspiro[3.3]heptan-2-carboxylic acid tert-butyl ester (530 mg, 693 μηιοί) was combined with dioxo (15 ml) and 1 M LiOH (3 ml) to give a dark brown solution. The reaction mixture was stirred at 25 ° for 4 hours. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut elut (M+H)+=723 m/e. NMR (300 MHz, chloroform-d) δ: 8.36 (s, 1 Η), 8.26 (d, J = 2.6 Ηζ, 1 Η), 8.19 (s, 1 Η), 7.37-7.69 (m, 6H), 6.84-6.94 ( m,1H), 6.80 (d, J=3.0 Hz, 1H), 4.39 (d, J=6.8 Hz, 2H), 4.08 (s, 4H), 3.96 (s, 4H), 3.85 (s, 3H), 1.42 (s, 9H), 1.39 (s, 9H). Step 6. Preparation of 6-t-butyl-2-(3_{5-[5-(2,6-diaza-spiro[3.3]hept-2-yl)-pyridin-2-ylamino]- 1-methyl-6-sideoxy_i,6-dihydro-pyridazine_3_yl}_2_hydroxymethyl-phenyl)-8-fluoro-2H-pyridazinone 157475.doc -171· 201211039

S '6-(6-(6-(3-(6-T-butyl-8-fluoro-1-yloxypyridazin-2(1H)-yl)-2) in a 250 mL round bottom flask -(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diaza Spirulina [3.3] Glycidyl-2-carboxylic acid tert-butyl ester (169 mg, 234 μηιοί) was combined with DCM (10 ml) and TFA (2 ml) to give a yellow solution. The reaction mixture was stirred at 25 ° C for 1 hour. Concentration in vacuo gave the title compound as a yellow solid. (M+H)+=623 m/e. Example 22 Step 7. Preparation of 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{l-fluorenyl-5-[5-(6-fluorenyl-2,6-di) Aza-spiro[3.3]hept-2-yl)-pyridin-2-ylamino]-6-sideoxy-1,6-dihydro-indole _3_yl}-phenyl)-2H -d 嗓-1-one

2-(3-(5-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-ylamino))indolyl in a 25 mL round bottom flask _6_Sideoxy-1,6-dihydropyridazine-3- 157475.doc 172· 201211039 base)_2_(methyl)phenyl)-6-tert-butyl-8-fluoro-blow-1 (2H)-ketone (146 mg ' 234 μιηοΐ), 30% furfural (42.2 mg, 38.8 μb 1.41 mmol) and sodium cyanodehydride (177 mg, 2.81 mmol) in combination with methanol (9 ml) Solution. The reaction mixture was stirred at 25 ° C for 4 hours. The crude reaction mixture was concentrated in vacuo, diluted with 10 mL 0·1 M NaOH and extracted with DC The organic layer was dried over NaJO4 and concentrated in vacuo. By flash chromatography (40 g, containing 0% to 1% Me〇H)

DCM) Purification of the crude material. The pale yellow powder was dried under vacuum for 3 hours to give 0.33 g (22%) of the title compound (M+H = 637 NMR (300 MHz, chloroform-d) 8.37 (s, 1H), 8 28 (4) 2 2 Hz, 1H), 8.13 (s, 1H), 7.38-7.71 (m, 6Η), 6.75-6.93 (m, 2H), 4.40 (s, 2H), 3.96 (s, 4H), 3.88 (s , 3H), 3.47 (s, 4H), 2 37 (s, 3H), 1.42 (s, 9H). ' Preparation 1-23 Step 1. Dicyclopentan-1-yl)- Preparation 5 Preparation 2-(2,2,5,5-Tetramethyl-[1,2,5]azapyridine: sVSi:

Br in a 500 mL three-necked flask, 5_ desert

夂月女(5 2 , 9 RQ mm〇1) combined with THF (80 ml) (g 8·9 - aeronautical, and added with n-butyl group via syringe to cool to lt; hexane (18, 2 m b 157475.doc -173- 201211039 29.2 mmol). The reaction was stirred at -78 °C for 1 hour, then 1,2-bis(chlorodimethylindenyl)ethane (6.22 g, 28.9) was added dropwise over 15 minutes. Methyl) hexanes (18.2 ml, 29.2 mmol) containing n-butyllithium were added after 90 min of stirring at _78 ° C. The reaction was allowed to warm to 25 ° C and stirred for 2 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc (EtOAcjjjjjjjj Hg, 170 ° C) Purified crude brown oil. The product was crystallised to crystals crystals crystals crystals crystals crystalsssssssssssssssssssssssssssss (d, J = 2.6 Hz, 1H), 7.47 (dd, J = 8.9, 2.5 Hz, 1H), 6.47 (d, J = 8.7 Hz, 1H), 0.83 (s, 4H), 0.24-0.38 (m, 12H) » Step 2. Preparation of 5-(ethylthio)pyridine 2 -amine

5-Bromo-2-(2,2,5,5-tetradecyl-1,2,5-azaindole-5-yl)pyridine (5 19) in a 100 mL round bottom flask Mg, 1.65 mmol), ethanethiol (102 mg '122 μΐ '1_65 mmol), xantphos (47.6 mg, 82.3 μηιοί) and Hugh's base (425 mg, 575 μΐ, 3.29 mmol) with dioxane (10.0 ml) ) Combine to give a pale yellow solution. Pd2(dba)3 (37.7 mg '41.1 μπιοί) was added, and the mixture was evacuated and filled with argon gas. The reaction was heated to 157475.doc -174 - 201211039 and the mixture was stirred at 11 ° C and maintained under argon for 17 hours. The mixture was cooled to 25 ° C and concentrated in vacuo. The residue was partitioned between 1 M HCl and diethyl ether. The aqueous phase was separated and the aqueous phase was basified with 3 M NaOH. The aqueous layer was extracted with EtOAc (2×l 25 mL). The organic layer was combined, washed with EtOAc EtOAc EtOAc EtOAc The oil was dried under vacuum at 251 overnight to give an orange gum which was used in crude material for subsequent oxidation. (M+H)+=155 m/e. Step 3. Preparation of 5-(ethanesulfonyl)-pyridin-2-amine

'5-(ethylthio)βpyridin-2-amine (254 mg ' 1.65 mmol), TFA (376 mg, 254 pL, 3.29 mmol) and cardiac CPBA (625 mg ' in a 25 0 mL round bottom flask 3.62 mmol) combined with DCM (6 mL) gave a pale yellow solution. The reaction mixture was stirred at 0 °C for 2 hours. The thick suspension was quenched with aqueous Na2S03 and diluted with DCM. The phases were separated and the aqueous layer was back extracted with DCM (2 &gt;&lt; 2 〇 mL). The combined organic layers were washed with EtOAc EtOAc (EtOAc) Purification of the crude material by flash chromatography eluting elut elut elut elut elut elut eluting (M+H)+=187 m/e. NMR (300 MHz, 157475.doc -175- 201211039 chloroform-d) δ: 8.53 (d, J=2.6 Hz, 1H), 7.82 (dd, J=8.7, 2·3 Hz, 1H), 6.55 (d, J=8.7 Hz, 1H), 5.23 (br. s.5 2H), 3.09 (q, J=7.6 Hz, 2H), 1.29 (t, 3H). Step 4. Preparation of 6-chloro-4-(5-ethylidene-branched-to-bit-2-ylamino)_2_methyl-2H-° up to -3-

5-(Ethylsulfonyl)pyridine-2-amine (183 mg, 983 μιηοΐ), 4-indol-6-chloro-2-methylindole in a 250 mL round bottom flask. Qin _3(2ίί)-ketone (263 mg, 1.18 mmol), xantphos (85.3 mg, 147 μηιοί) and Cs2CO3 (960 mg' 2.95 mmol) were combined with dioxane (10 mL) to give a pale brown suspension. The flask was evacuated and filled with argon. Pd2(dba)3 (45.0 mg ' 49.1 μιηοΐ) ' was added and was at 1 Torr. (The reaction mixture was stirred under argon for 20 hours under argon. Cooled to 25 ° C and diluted with DCM. The reaction mixture was passed through EtOAc and washed with DCM until clarified. The filtrate was concentrated and purified by flash chromatography Purification of the title compound <RTI ID=0.0>(M+H) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; NMR (300 MHz, DMSO-d6) δ: 10.18 (s, 1H), 8.78 (d, J = 2.3 Hz, 1H), 8.12 (dd, J = 8.9, 2.5

Hz, 1H), 7.74 (d, J=9.1 Hz, 1H), 3.69 (s, 3H), 3.32 (q, 157475.doc •176· 201211039 J=7.4 Hz, 2H), 1.11 (t, J=7.4 Hz, 3H). Step 5. Preparation of 2-(6-t-butyl-8-fluoro-1-oxo-1H-pyridazin-2-yl)-6-[5-(5-ethanesulfonyl-pyridine) -2-ylamino)-1-indolyl-6-o-oxy-1,6-dihydro-pyridazin-3-yl]-phenylmethyl ester

6-Chloro-4-(5-(ethylsulfonyl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (79 mg in a 250 mL round bottom flask) ,240 μιηοΐ), 2-(6-t-butyl-8-fluoro-1-o-oxo-oxazine-2-(1Η)-yl)-6-(4,4,5,5-tetramethyl)acetate -1,3,2 - acetoacetamido-2-yl)benzaldehyde vinegar (154 mg, 3 12 μιηοΐ) and Cs2C03 (235 mg, 721 μηιοί) with dioxane (1 〇ml) and water (1 ml ) Combine 'to give a light yellow suspension. The mixture was evacuated and filled with argon. PdCl2 (DPPF) (9.81 mg, 12.0 μηιο1) was added, and the reaction mixture was purged with argon and heated to 85 ° C for 60 hours. The reaction mixture was diluted with DCM and filtered over EtOAc. The filter cake was washed with DCM until clear. The filtrate was dried over Na~~~~~ The brown oil was used in the crude reaction as a crude material. (MH)+=659 m/e 〇Example 23 Step 6. 157475.doc -177- 201211039 Preparation of 6-t-butyl-2-{3-[5-(5-ethanesulfonyl-pyridine-2 -ylamino)-^ fluorenyl-6-yloxy-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl•phenylfluoro-2 Η-嗓嗓-1-S

In a 250 mL round bottom flask, 2-(6-t-butyl-8-fluoro-1-oxo-oxetazine-2(1 H)-yl)-6-(5-(5-( Ethylsulfonyl)-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl ester (159 mg, 241 μιηοΐ) In combination with dioxane (5 ml) and 1 M LiOH (1 ml), a color solution was obtained. The reaction mixture was stirred at 25 ° C for 18 hours. The crude reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc EtOAc (EtOAc)

The title compound is obtained as a brown solid. (M_H)+=617 m/e. 4 NMR (300 MHz, chloroform-d) δ: 8.85 (d, J = 2.3 Hz, 1H), 8.79 (s, 1H), 8.63 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.06 (dd, J=8.7, 2.3

Hz,1H),7.43-7.73 (m,5H),7.07 (d,J=8.7 Hz,1H),4.45 (s, 2H),3.94 (s,3H),3.15 (d,J=7.2 Hz, 2H ), 1.44 (s, 9H), 1.33 (t, J = 7.2 Hz, 3H). Example 24 Preparation of 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{l-fluorenyl-6-oxirane-5-157475.doc •178· 201211039 [5-(丙烧-2-生酿基) "Bit bit_2·ylamino hydrazine, 6-dihydro-pyridazine_3_ phenyl phenyl)-2H-pyridazin-1-one &amp;

Borrowed by a procedure similar to that of Example 23, the action of the juice coat was replaced with propan-2-thiol instead of step 2

The title compound was obtained as a brown solid. (M+H)+=633 m/e. /H NMR (300 MHz, chloroform-d) δ: 8.81 (d, J = 2.3 Hz, 1H), 8.73-8.79 (m, 1H), 8.62 (s, 1H), 8.29 (d, J = 2.3 Hz, 1H), 8.04 (dd, J=8.7, 2.3 Hz, 1H), 7.43-7.70 (m, 5H), 7.07 (d, J=8.7 Hz, 1H), 4.45-4.59 (d, 2H), 3.94 (s , 3H), 3.21 (m, J=6.8 Hz, 1H), 1.44 (s, 9H), 1.34 (d, J=6.8 Hz, 6H). Preparation 1-25 Step 1. Preparation of 2-(6-Aminopyridine-3-ylthio)_ethanol

V

OH In a 1〇〇11^ round bottom flask, 5-bromo-2-(2,2,5,5-tetramethyl-1,2,5-aza-aza-cyclohexan-1-yl) . Ratio (502 mg, 1.59 mmol), 2-meryl 157475.doc • 179· 201211039 Ethanol (124 mg, 112 μΐ ' 1.59 mmol), xantphos (46.1 mg ' 79.6 μπιοί) and Hugh's base (411 mg) , 556 μb 3.18 mmol) combined with dioxane (10.0 ml) gave a pale yellow solution. Pd2(dba)3 (36.4 mg, 39.8 μηιοί) was added, and the mixture was evacuated and filled with argon. The reaction mixture was heated to 110 ° C and stirred under argon for 17 hours. The reaction mixture was cooled to 25 &lt;0&gt;C, concentrated in vacuo and partitioned between 1M EtOAc andEtOAc. The aqueous layer was separated and the aqueous layer was basified with 3 M NaOH. The aqueous layer was extracted with EtOAc (3×l 25 mL). The combined organic layers were dried with EtOAc EtOAc EtOAc EtOAc The solid was dried under vacuum at 25 °C for 21 hours to give 259 g (96%) of title compound. 1H NMR (300 MHz, DMSO-d6) δ: 7.94 (d, J = 2.3 Hz, 1H), 7.45 (dd, J = 8.7, 2.3 Hz, 1H), 6.40 (d, J = 8.7 Hz, 1H), 6.03-6.20 (m, 2H), 4.77 (t, J=5.7 Hz, 1H), 3.37-3.51 (m, 2H), 2.67-2.76 (m, 2H) 〇 Example 25 Step 2. Preparation 6 - Second Ding _8_Fluoro-2_(3_{5_[5-(2-hydroxyethylthio)-pyridine-2-aminocarbyl]-1-methyl-6-yloxy-oxime, 6-dihydro-pyridazine Keb 2_hydroxyindole _ phenyl)-2H-blowing

157475.doc 201211039 2-(6-Aminopyridin-3-ylthio)ethanol (247 mg, 1.45 mmol), 2-(5-bromo-1-methyl-acetate) in a 250 mL round bottom flask 6-Sideoxy-1,6-dihydropyridazin-3-yl)-6-(6-t-butyl-8-fluoro-1-oxophthalazine-2(1H)-yl) The oxime ester (806 mg, 1.45 mmol), xantphos (126 mg, 218 μιηοΐ), and Cs2C〇3 (1.42 g, 4.35 mmol) were combined with dioxo (20 ml) to give a brown suspension. The reaction was evacuated and filled with argon. Pd2(dba)3 (66.4 mg '72.5 μηιοί) was added, and the reaction mixture was heated to 1 ° C and stirred under argon for 17 hours. Cool to 25 ° C and dilute with DCM. The reaction mixture was filtered through celite, and the filter cake was washed with DCM and evaporated. The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc, 40 g, DCM The material was re-purified by flash chromatography (40 g, 〇% to 50% acetone in heptane) and concentrated to a white powder in vacuo and dried overnight at 25 ° C under vacuum. The product was dissolved in dioxane (15 ml) and 1M LiOH (3 ml) was then applied. The reaction was stirred at 25 ° C for 17 hours. The crude reaction mixture was concentrated in vacuo. The residue was diluted with 15 mL DCM and 15 mL EtOAc. The aqueous layer was back extracted with DCM (2 x 20 mL). The organic layer was dried over Naa SCU and concentrated in vacuo. Purification of the crude material by flash chromatography <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; (M+H)+=603 m/e. 4 NMR (300 MHz, chloroform-d) δ: 8.61 (s, 1 Η), 8.42 (d, J = 2.3 Hz, 1H), 8.38 (s, 1H), 8.29 (d5 J=2.6 Hz, 1H), 7.73 (dd, J=8.5, 2.5 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.53-7.57 (m, 2H), 7.45-7.51 ( m, 1H), 6.95 (d, J=8.3 Hz, 1H), 4.43 (s5 2H), 3.92 (s, 3H), 157475.doc -181· 201211039 3.74 (t, J=5.9 Hz, 2H), 3.04 (t, J = 5.9 Hz, 2H), 1.43 (s, 9H). Example 26 Preparation of 6-t-butyl _8-^-2-(3-{5-[5-(2-light-based ethoxylate)-0-pyridin-2-ylamino]-1- Methyl-6-o-oxy-1,6-dihydro-pyridazin-3-yl}-2-hydroxyindolyl-phenyl)-2H-phthalazin-1-one

In a 100 mL round bottom flask, 6-t-butyl-8-fluoro-2-(3-(5-(5-(2-hydroxyethylthio).pyridin-2-ylamino) -1-methyl-6-o-oxy-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)pyridazine-1(2H)-one (45 mg, 74.7 Ηηιοί) combined with DCM (4 ml) gave a pale yellow solution. The mixture was cooled to 〇 ° C, and TFA (17.0 mg, 11 · 5 μΐ, 149 μηιοί) and 111-CPBA (28.3 mg, 164 μηιοί) were added. The reaction was stirred at 0 °C for 3 hours. The reaction was quenched with saturated Na2SO3 and 1 M NaOH. Dilute (milk) with DCM and separate. The aqueous layer was back extracted with DCM (3 x 20 mL). The combined organic layers were washed with EtOAc EtOAc (EtOAc) Purification of the crude material by flash chromatography eluting EtOAc (EtOAc:EtOAc: (M+H)+=634 m/e. 4 NMR (300 MHz, gas-sentence-sentence δ. 8.87 (d, J=2.3 Hz, 1H), 8.80 (s, 1H), 8.66 (s, 1H), 8.3 〇 (d&gt; 157475.doc -182- 201211039 J=2.3 Hz, 1H), 8.07 (dd, J=8.7, 2.6 Hz, 1H), 7.45-7.68 (m, 5H), 7.08 (d, J=8.7 Hz, 1H), 4.45 (s, 2H), 4.01-4.09 (m, 2H), 3.93 (s, 3H), 3.34-3.42 (m, 2H), 1.44 (s, 9H). Preparation 1-27 Example 27 6-t-butyl-8·fluoro-2 -(2-hydroxymethyl-3-{5_[5_(4-isopropyl-piperazine-yl)-° ratio -2-ylamino]-1-methyl-6-sideoxy-if Dihydro-indenyl}-phenyl)-2H-phthalazin-1-one hydrochloride

Step 1. To a solution containing 5-bromo-2-nitropyridine (1.0 g ' 4.93 mmol, 1.00 eq.) in DMSO (10.0 ml) was added 1·isopropylpiperazine (632 mg, 4 93 mm 〇1, 1 〇〇 〇〇 look :) 'and heat the resulting solution at 70 C for 18 hours ◎ Cool the solution to room temperature. Dilute the solution with 50 ml of water. The resulting solid was filtered. The solid was washed with water and dried under vacuum. The crude material was purified by flash chromatography (EtOAc, EtOAc EtOAc EtOAc EtOAc Beta azine (788 mg '64%). Observed by LC/MS-ESI [M+H] + 251. 157475.doc -183· 201211039 Step 2. In a 250 mL round bottom flask, the 丨_isopropylpyridinium pyridine group (788 mg, 3.15 〇 〇 1 〇〇 equivalent) Et〇H (4 〇 is combined with palladium/carbon (DeGussa) (78.2 mg '735 μιηοο 0.233 eq.). The mixture was evacuated twice with hydrogen, followed by stirring under hydrogen atmosphere for 18 hours. Washing the diatomaceous earth with fresh ethanol The solution was filtered through celite, and the solvent was evaporated under reduced pressure to give 5-(4-isopropylpiperazinyl). <RTIgt; </RTI> </RTI> <RTIgt; Value [M+H] + 221. Step 3. In a 50 mL round bottom flask, 5-(4-isopropylpiperazine-indolyl)pyridine was added to the amine (200 mg, 908 μΓη〇b1·〇) 〇 equivalent), 4_ bromo 2 曱 曱 哒 _ _ 3(2Η)-one (243 mg, 1.09 mmol '1.2 eq) and cesium carbonate (887 mg ' 2.72 mmo b 3 equivalents) and dioxane ( 20 mi) combination to give an orange suspension. Add 4,5-bis(diphenylphosphino)-9,9-diindenyl dipyridamole. South (78.8 mg, 136 μιηοΐ, 0.15 eq.). (diphenylmethyleneacetone) two (0) (41.6 1^, 45 .4 4111 〇 1, 0.05 eq.) Degas the solution for 10 minutes with 八 1 '. Heat the solution at 95-105 ° C for 48 hours. Dilute the solution with 200 ml of DCM. Add MgS 〇 4 ' and stir the suspension 1 The mixture was washed with EtOAc (m.). -(5-(4-isopropyl. oxa-1-yl)"pyridin-2-ylamino)_2-mercaptopyridazine-3(2H)-one (273 mg, 83%). LC /MS-ESI observed [M+H]+ 363. Step 4. 157475.doc •184· 201211039 6-Chloro-4-(5-(4-isopropylpiperazine-i-yl)D-pyridyl -2-ylamino)_2-mercaptopyridazine-3(2H)-one (123 mg, 340 μιηοΐ, 1.2 eq.), 2-(6-t-butyl-8-fluoro-1-oxoacetate Pyridazine_2(lH)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-di-mil-2-pyrene-2-yl)benzaldehyde (140 mg, 283 Ιιηοΐ, 1.00 eq.), tripotassium phosphate (180 mg, 850 μηηοΐ, 3.00 eq.) and again-PHOS (13.5 mg ' 28.3 μηιοί, 0.10 equivalent) dissolved in dioxane (1 〇ml) and water (1.0 mL) . The reaction was degassed with Ar. Pd2(dba)3 13.0 mg, 14.2 μηηοΐ '0.05 equivalent) was added, and the reaction was heated to 125 ° C for 30 minutes in a microwave. The solution was dried over MgS04 and filtered. Concentrate in the sky. The crude material was purified by flash chromatography (12 g, 〇〇/〇 to 50/〇MeOH/DCM gradient) to give 2-(6-t-butyl-8- Base ° too α-Qin-2(1H)-yl)-6-(5-(5-(4-isopropyl-benzin-1-yl) ° ratio. 1,4--2-ylamino)-1-methyl Keto-6-o-oxy-1,6-dihydrooxazin-3-yl)benzyl ester (153 mg, 78%). Observed by LC/MS-ESI [M+H]+ 695. Step 5 · To 2-(6-t-butyl-8-fluoro-1-oxophthalazine-2-(1H)-yl)-6-(5-(5-(4-isopropyl) acetate) Piperazine-i-yl)pyridine_2-ylamino)-丨-mercapto_6_sideoxy-1,6-dihydropyridazin-3-yl)benzyl ester (153 mg, 220 μηιοί, A 1 N aqueous NaOH solution (2.0 mL, 2.00 mmol, 9.08 eq.) was added to EtOAc. The resulting solution was heated at 60 ° C for 2 hours. The mixture was cooled to room temperature. The solution was diluted with saturated NaHC03 and DCM. Separate the layers. The aqueous layer was extracted three times with DCM. The combined organics were dried over MgS04. Filter the solution. Concentrate in vacuo. By flash chromatography (矽g, 12 g, 0% to 50% (60··10··1 DCM: MeOH..NH4〇H)/DCM gradient) pure 157475.doc •185· 201211039 Milky white solid. The solid was wet-ground with Ε^Ο. The over-solids were then dissolved in 2 ml of DCM. Add 1.0 M of HC1 to Et 2 〇 (solution in 2. Form a solid. Filter the solid and dry under vacuum to give 6-t-butyl-8-fluoro-2-(2-hydroxydecyl-3-{5- [5-(4-Isopropyl-piperazine-indolylpyridin-2-ylamino]-1-indolyl-6-yloxy-1,6-dihydro-pyridazin-3-yl }-Phenyl)-2H-pyridazine-bupropion hydrochloride (5 7.5 mg, 38%). LC/MS-ESI observed [M+H]+ 653. NMR (300 MHz, DMSO- &lt;i6 δ ppm 1.28 (d, 7=6.80 Hz, 6 H) 1.37 (s, 9 H) 3.08 (d, 7=11.33 Hz, 2 H) 3.46 (d, 7=10.20 Hz, 2 H) 3.76 (s, 5 H) 4.39 (d, /=6.04 Hz, 2 H) 7.41-7.59 (m, 5 H) 7.73 (d, 7=13.97 Hz, 1 H) 7.86 (s, 1 H) 8.06 (d, *7= 2.27 Hz, 1 H) 8.42 (s, 1 H) 8.50 (d, 7 = 2.27 Hz, 1 H) 9.31 (s, 1 H) Preparation 1-28 Example 28 6-Ter Butyl-8-Fluoro-2 -(2-hydroxymethyl-3-{l-methyl-5-[5-(l-methyl-pyrazin-3-yl)-pyridin-2-ylamino]-6-sideoxy -1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-pyridazine-I-ketone

Step 1. 157475.doc -186 201211039 THF (5.6 ml ' 5.6 mmol, 1.07) in a 100 mL three-necked flask with 1 μ bis (trimethyl sulfhydryl) aminating at -78 ° C. Equivalent) A solution of 3-tert-oxypyrrolidine-1-decanoic acid tert-butyl ester (1 g, 5.24 mmol, 1 〇〇 eq.) in THF (30.0 mL). At _78. (After stirring for 15 minutes, a solution of N-phenylbis(trifluorodecanesulfonimide) (2 27 g, 6 28 mmol, 1.20 equivalent) in THF (10 ml) was added dropwise. The reaction mixture was warmed to room temperature. The reaction was quenched with EtOAc EtOAc EtOAc EtOAc EtOAc. The crude material was purified by chromatography eluting with EtOAc/Hex (EtOAc/Hex gradient) to afford 3-trifluoromethanesulfonyloxy-2,5-dihydro-pyrrole-1-decanoic acid tert-butyl ester ( 880 mg, 53%) Step 2. '3-Trifluorodecanesulfonyloxy-2,5-dihydro-pyrrole-1-decanoic acid tert-butyl ester (780 mg) in a 25 mL round bottom flask ' 2.46 mmo 1 〇〇 ) )) combined with THF (20 ml) to give a colorless solution. Purify the solution with argon for a few minutes. Add potassium carbonate (1.72 g, 12.3 mmol, 5_0 equivalent), 5- (4, 4,5,5-Tetramethyl-1,3,2-dioxaborom-2-yl)pyridin-2-amine (649 mg, 2.95 mmol ' 1.20 equivalent), hydrazine (triphenylphosphine) palladium ( 0) (28.4 mg, 24.6 μπιοί '0.01 equivalent) and water (200 μΐ) The reaction mixture was heated to 70 ° C and stirred for 16 h. The reaction mixture was poured with EtOAc EtOAc EtOAc (EtOAc m. The crude material was purified by flash chromatography (EtOAc:EtOAc (EtOAc:EtOAc) Dihydro-pyrrole-1-carboxylic acid tert-butyl ester (538 mg, 84%) 157475.doc •187· 201211039 LC/MS-ESI observed [M+H]+ 262. Step 3, 3-(6) -Amino-0 to acetyl-3-yl)-2,5-diaza-β than oxime-i-carboxylic acid tert-butylate (53 8 mg '2.06 mmol, 1.00 equivalent) dissolved in sterol (20 ml The solution was placed under argon' followed by treatment with palladium/activated carbon (43.8 mg, 20.6 μιηοΐ, 〇·〇1 equivalent). The suspension was purged with hydrogen and stirred under hydrogen for 18 hours. The reaction mixture was concentrated, and the residue was dissolved in EtOAc (EtOAc) (EtOAc) (EtOAc) Purify with hydrogen The suspension was suspended and sampled under hydrogen for 18 hours. The reaction mixture was filtered through a 45 μm glass frit. The filtrate was concentrated in vacuo to give &lt;RTI ID=0.0&gt;&gt;&gt; Observed by LC/MS-ESI [M+H]+ 264. Step 4. 3-(6-Aminopyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (422 mg, 1.6 mmol '1.00 equivalent), 4-bromo-6-chloro-2-indenyl Pyridazine-3 (2 ketone-ketone (430 mg, 1.92 mmol, 1.20 eq.), 4,5-bis(diphenylphosphino)- 9,9-dimercaptodibenzopyran (139 mg '240) Μιηοΐ, 0.15 eq.), carbonic acid planing (1.57 g ' 4.81 mmol, 3 equivalents) and ginseng (diphenylidene acetonide) dipalladium (0) (73.4 mg, 80.1 μηιοί, 0.05 eq.) in dioxane (10 ml) The solution was degassed for 10 minutes with Ar. The mixture was heated at i ° ° C for 18 hours. The solution was cooled to room temperature and then diluted with 100 ml of DCM. The organics were washed with water and then dried over MgSO. Concentration in vacuo. Purification of the crude material by flash chromatography (EtOAc: 40 g, 50% to 100% EtOAC/Hex 157475.doc: 188 _ 201211039) to give 3-(6-(6-gas-2- Methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-furic acid tert-butyl ester (325 mg, 50%). Observed for LC/MS-ESI [M+H] + 406. Step 5. 3-(6-(2-chloro-2-methyl-3- oxo-2) , 3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (160 mg, 394 μηιοί, 1.00 equivalent) dissolved in formic acid (6.0 ml) and 37% The solvent mixture of formaldehyde (12.0 ml) was stirred at 70 ° C for 18 hours. The solution was cooled to room temperature. "Water was added. The reaction mixture was extracted once with DCM. The solid K2C03 was slowly added to the aqueous layer until pH = 14. A solid is formed, followed by filtration. The solid is dried to give 6-chloro-2-methyl- 4-(5-(1-methyl-O-Butyl-3-yl)-pyridin-2-ylamino)pyridazine- 3(2Η)-ketone (70 mg, 55%). LC/MS-ESI observation [Μ+Η]+ 320 ° Step 6. In the 50 mLs formula, '6-chloro-2-indenyl- 4 - (5-(1-methyl. piroxime _3_ base) ° 唆-2-ylamino) 达-3(2H)-one (69 mg, 216 μηιοί, 1.00 equivalent) and acetic acid 2- (6-Tertibutyl-8-fluoro-1-oxo-oxazine-2(1Η)-yl)-6-(4,4,5,5-tetradecyl-1,3,2-di Boronol-2-yl)benzoquinone (128 mg, 259 μηηοΐ, 1-20 equivalent) was combined with BuOH (4 ml) to give an orange solution. Water (1.0 ml), X-PHOS (10.3 mg, 21.6 μηιοί, 〇.1 equivalent) and acid slant (91.6 mg ‘ 432 μηιοί ' 2 equivalents) were added in that order. Add bis(dibenzylideneacetone) (6.2 mg, 10.8 μιηοΐ, 0.05 equivalent). Clean the solution with chlorine. The reaction mixture was warmed in an oil bath at 110 ° C for 1.5 hours to "cool the solution to room temperature. The reaction mixture was poured into 75 mL of H.sub.2, and 157. The organic layer was concentrated in vacuo. By flash chromatography (矽

Glue, 12 g, 50% to 1 〇〇〇 /0 (60:10:1 DCM: MeOH: NH4OH) / DCM gradient) Purified crude material to afford product acetic acid 2 _ (6 _ _ _ _ _ _ _ _丨_sideoxy.Tetazine-2(1H)-yl)-6-(1-indolyl-5-(5-(1-methyl-pyrrolidin-3-yl) ° ratio bit -2- Amino group-oxyl-i,6-dihydroindole.Qin-3-yl)benzyl ester and 6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3·{1- Mercapto-5-[5-(l-fluorenyl-pyrrolidino-3-yl)_°pyridin-2-ylamino]-6-o-oxy-1,6-dihydro-pyridazine-3 a mixture of -yl}-phenyl)-2H-»Tetazine-indole-ketone (ratio 1:7, total 109 mg, total 75%). LC/MS-ESI observed [M+H]+ 652, 610 Step 7. To 2-(6-t-butylfluoro-1-l-oxyphthalazin-2-(ih)-yl)-6-(1-indolyl-5-(5-(1-oxime) acetate Pyrrrolidine _3_yl)pyridine-2-aminocarbyl)-6-sideoxy-1,6-dihydropyridazin-3-yl)benzoin and 6-t-butyl-8-fluoro- 2-(2-Hydroxyindol-3-{l-fluorenyl-5-[5-(1_indolylpyrrolidinyl-3-yl)-pyridin-2-ylamino]-6-sideoxy -1,6-Dihydro-pyridazine_3_ylbuphenyl)_2Η_pyridazine-butanone (1〇6 mg' 163 μηιοί, 1_〇〇 equivalent) in a mixture of thF (2.0 ml) Add to 1 N NaOH aqueous solution (1.95 ml, 1.95 mmol, 12.0 eq.). The mixture was heated to 60 C for 18 h. The solution was cooled to room temperature. The solution was diluted with saturated NaHC 3 and DCM. The mixture was dried over EtOAc (EtOAc m. Third butyl _8_fluoro-2_(2-hydroxyindole-3-{l-fluorenyl-5-[5-(1-methyl-pyrrolidinyl)-3-yl)-2-pyridine-2-amine ]]-6-Sideoxy-1,6-dihydro-pyridazine, 3-phenyl}-phenyl)_2H-pyridazine-indole-ketone (41 157475.doc -190-201211039 mg, 41%). Observed by LC/MS-ESI [M+H]+ 610. 4 NMR (300 MHz, chloroform-c/) δ ppm 1.45 (s,9 Η) 1.86 (dd,·7=13.03, 6.99 Hz, 1 H) 2.23-2.60 (m,5 Η) 2·76 (br. s.,2 H) 3.00 (br. s·,1 H) 3.24-3.42 (m, 1 H) 3.91 (s, 4 H) 4.43 (d , 7=6.04 Hz, 2 H) 6.92 (d, /=8.31 Hz, 1 H) 7.40-7.78 (m, 6 H) 8.26 (dd, J=12.65, 2.83 Hz, 3 H) 8.62 (s, 1 H 〇Preparation 1-29 Example 29 6-Terbutyl-8-fluoro-2-{2-hydroxymethyl-3 -[5-(l,-isopropyl-1',2',3',4',5',6'-hexahydro-[3,4,]bipyridine·6-ylamino)-1 -Methyl-6-o-oxy-1 &gt;6-.-indol-3-yl]-phenyl σ-qin-1-

Step 1. In a 50 mL round bottom flask, 5-bromo-2-nitropyridine (3.28 g, 16.2 mmol, 1 eq.) and 4-(4,4,5,5·tetramethyl-1,3 , 2_dioxaboron-2-yl)_ 5,6-dihydrobite-1 (2Η)-citrate third vinegar (5 g, 16 2 _〇1, i 〇〇 equivalent) and two The methane (80_0 ml) was combined to give a pale yellow solution. Add to

Cs2CO3 (10.5 g, 32.3 mmo b 2 equivalents) and 3 ho. The solution of 157475.doc -191 . 201211039 was degassed with Ar, followed by the addition of di-gasified bis(triphenylphosphine)palladium (丨 13 g, 1.62 mmol, 0.1 eq.). The reaction mixture was heated to and mixed for 15 hours. The reaction mixture was poured with EtOAc (3×100 mL). The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut The solid was wet-milled with Ε^Ο to give 4-(6-nitro.by -3-yl)-5,6-dihydrogen ratio bite-1(2H)-carboxylic acid tert-butyl as a brown solid. Ester (685 mg '69%). Observed by LC/MS-ESI [M+H]+ 306. Step 2. In a 250 mL round bottom flask, 4-(6-nitropyridin-3-yl)-5,6-dihydro 0-pyridine-1(2H)-carboxylic acid tert-butyl ester (632 mg) , 2.07 mmol, 1.00 eq. of EtOH (25.0 ml) and ethyl acetate (10 ml) were combined with palladium/carbon (66.1 mg, 62·1 μηιοί ' 0.03 equivalent). The mixture was evacuated twice with hydrogen and then stirred under a hydrogen-filled balloon for 22 hours. The solution was filtered through celite. The diatomaceous earth was washed several times with EtOAc. Concentration in vacuo gave 4-(6-aminopyridin-3-yl)piperidine-1-furic acid tert-butyl ester (635 mg, quantitative yield). Observed by LC/MS-ESI [M+H]+ 278. Step 3. 4-Bromo-6-gas-2-methylpyridazin-3(2H)-one (509 mg, 2.28 mmol, l.oo equivalent), 4-(6-amino) under argon Pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl (632 mg, 2.28 mmol, 1.00 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyldiphenyl Piper (198 mg, 342 μηιοb 0.15 equivalent) and carbonic acid planer (2.6 g, 7.98 mmol, 3.5 equivalents) were suspended in dioxane (20 157475.doc -192.201211039 ml). Finally, ginseng (diphenylmethyleneacetone) dipalladium (rhodium) (i56 mg, 171 μιηοΐ, 0.075 equivalent) was added. The reaction mixture was heated to 90 ° C for 18 hours. The reaction mixture was filtered through celite, washed with dioxane and concentrated in vacuo. The crude material was purified by flash chromatography eluting eluting elut elut elut elut elut elut elut -Dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (782 mg, 82%). Observed by LC/MS-ESI [M+H]+ 420. Step 4. To 4-(6-(6- oxa-2-mercapto-3-oxo-2,3-dihydropyridazin-4-ylamino) 0--3-yl) hydrazine TCA (2.12 g, 1.43 m, 18.6 mmol, 10 eq.) was added to EtOAc (EtOAc, EtOAc (EtOAc) The reaction mixture was stirred under nitrogen for 18 hours. Concentration in vacuo gave 6-Gas-2-methyl-4-(5-(peptid-4-yl)β-buty-2-ylamino)pyridin-3(2Η)-one (474 mg, 80%). Observed by LC/MS-ESI [Μ+Η] + 320. Step 5. To 6-Gas-2-methyl-4-(5-(0-But-4-ylbi-2-amino)- to-Qin-3(2Η)-one (200 mg, 625) Ππιοί, 1.00 eq.) and a solution of propylene ((799 mg, 1.01 m, 13.8 mmol, 22 equivalents) in MeOH (5 ml) were added to a solution of thiophene hydride (39.3 mg, 625 μηηοΐ, 1.00 eq.) and acetic acid ( 65 6 mg, 625 μΐ, 10.9 mmol, 17.5 eq.) The reaction mixture was stirred for 18 hours under Ν 2. Acetone (1 ml) was added followed by THF (3 m 1). 2 hours. Add the base side gasification sodium (19.7 mg, 313 μηηοΐ, 0.50 equivalent). Stir the mixture 4 small 157475.doc -193- 201211039. Concentrate in vacuo. By flash chromatography (矽, 12 g 50% to 100% (60:10:1 ϋ〇νΐ:Μ6〇Η:ΝΗ4ΟΗ)/ΟΟΜ gradient) Purification of the crude material 'to give 6-chloro-4- (5-(1-isopropyl) 4-yl)β-Bist-2-ylamino)-2-methylpyridazin-3(2Η)-one (220 mg, 97%). LC/MS-ESI observed [M+H]+ 362 ° Step 6. In a 50 mL tube, 6-gas-4-(5-(1-isopropylpiperidine, 4-yl). Bis-2-ylamino -2-mercaptopurine °-3(211)-ketone (220 mg, 608 μπιοί, 1.00 equivalent) and 1703,100 (288 mg, 608 μηιοί, 1.00 eq.) were combined with 811〇11 (12.9 1111). Add water (3.24 1111), add -?11〇3 (29.0 mg '60.8 μηιοί, 0.1 eq.) and tripotassium phosphate (258 mg, 1.22 mmol '2 eq.). Add bis(diphenylarhenylidene)palladium (ΐ7·5 mg, 3 0·4 μηιοί, 0.05 equivalent). The solution was purged with argon. The reaction was warmed in an oil bath for 18 hours at 10 ° C. The solution was allowed to cool to room temperature. The mixture was poured into 75 mL of H20 and extracted twice with EtOAc. EtOAc (EtOAc) EtOAc EtOAc EtOAc 60:10:1 DCM: MeOH:NH4OH) / CM gradient) EtOAc (EtOAc: EtOAc: -6-(5-(5-(1-isopropylpiperidin-4-yl). Bipyridin-2-ylamino)-1-indolyl-6-o-oxy-i,6-dihydroindan-3-yl)benzoin (248 mg '59%). Observed by LC/MS-ESI [M+H]+ 694. Step 7. To 2-(6-t-butyl-8-fluoro-indole-oxo-oxazine-2(1H)-yl)-6-(5-(5-(1-isopropyl)piperidinate) Acridine·4-kibidine-2-ylamino)-1-methyl-6-sideoxy 157475.doc -194· 201211039 yl-1,6-dihydropyridazine-3-yl)benzyl ester ( 248 mg, 357 μηιοί, 1.00 eq.) THF (5. 〇mi) was added Na 〇H (4.29 ml, 4.29 mmol '12.0 eq.). The reaction mixture was heated at 6 ° C for 18 hours. The mixture was diluted with saturated NaHC03 and DCM. The layers were separated. The aqueous layer was extracted three times with DCM. The organic layer was combined and then dried over Na.sub.2 g. 6-tert-butyl-8-fluoro-2]2-hydroxymethyl_3_[5_(Γ_isopropyl)

1·, 2', 3', 4', 5·, 6'-hexahydro-[3, 4']. Bipyridin-6-ylamino)-1-methyl-o-oxy-1,6-dihydro-indole-3-yl]-phenyl}-2indole-pyridazine ketone (2〇2 mg, 87 %). Observed by LC/MS-ESI [M+H]+ 652. NMR (300 MHz, chloroform J) δ ppm 1.10 (d, "7=6.42 Hz, 6 Η) 1.43 (s,9 Η) 1.84 (br. m·,5 Η) 2.28 (br. m.,2 Η) 2.50 (br. m.,1 Η) 2.79 (br. s., 1 H) 3.03 (d, /=10.20 Hz, 2 H) 3.90 (s, 4 H) 4.42 (d, /=6.80 Hz, 2 H 6.92 (s, 1 H) 7.40-7.73 (m, 6 H) 8.17-8.32 (m, 4 H) 8.60 (s, 2 H) Preparation of I-3〇 (2-(ethyloxycarbonyl) _3_(6_Terbutyl _8_Fluorine_丨_Sideoxypyridazine-2(1H)-yl)phenyl)trifluoroborate:

To a round bottom flask equipped with a bubbler, a thermometer and a magnetic stirrer was fed with 2-(6-t-butyl-bufluoro-indole-side oxetazine X-gas 157475.doc.195- 201211039 Phenyl phthalate (10 g, 24.8 mmol, 1.00 eq.), 4,4,4',4,5,5,5,5,-octamethyl-2,2,-linked (1,3, 2-Byroboron) (9.46 g, 37.2 mmo, 1.5 equivalents), Pd(OAc)2 (69.7 mg, 310 μιηοΐ '0.0125 eq.), and -PHOS (296 mg '621 μηαοί, 0.025 equivalent) and potassium acetate (5_29 g, 53.9 mmol, 2.17 eq.). The reaction mixture was degassed (3 times). MeTHF was added, followed by degassing again (3 times). The mixture was heated overnight at 60 ° C. The reaction was not completed. To 65 ° C, and stirred for 3 hours. HPLC showed the reaction was completed. The reaction was cooled and 2 N HCl (31.0 ml, 62.1 mmol, 2.5 eq.) was added. The mixture was stirred for half an hour, followed by embolization through diatomaceous earth to remove Separate the layers. The organic layer was washed with water (6 g, 60.0 ml) and then concentrated to the oil. The oil was dissolved in MeOH (79.2 g, 100 ml). And treated with 3 Μ potassium fluorohydride solution (20.7 ml, 62.1 mm ,l, 2.5 eq.). LC showed that the reaction was not completed overnight. An additional 0.5 eq of KHFs was added. The resulting slurry was warmed at 45 ° C for 3 hours at room temperature. The mixture was stirred overnight. The product was isolated by filtration. The filter cake was washed with decyl alcohol. After drying in vacuo, (2-(ethyloxymethyl)_3_(6-t-butylfluoro-l-yloxy oxime) was obtained. Potassium-2(1H)-yl)phenyl)trifluoroborate (11 26 light, 23.7 mmol, yield 95.6%). Example 30 Preparation of 6-t-butyl-2-{3-[5-(1) ·-Ethyl-Γ,2,,3Ι,4,,5,6,hexahydro[3,4,]bipyridin-6-ylaminoindenyl_6_sideoxy-丨,6_二Hydrogen-pyridazinyl]-2-hydroxymethyl-phenyl}-8-fluoro-2-indole-pyridazinone 157475.doc •196· 201211039

Step 1. In a 100 rtiL round bottom flask, '6-chloro-2-indolyl- 4-(5-(Niang. 1,4-yl). ° 定-2-ylamino) 嗓-3 (2H)-ketone (179 mg, 560 μιηοΐ, 1.00 eq.) and acetaldehyde (247 mg, 316 μM, 5.6 mmol, 10.0 eq.) were combined with hexane (5. 〇1111) to give a pale yellow solution. Acetic acid (33,6 11^, 32·0 μΐ, 5 60 μηιοί, 1.00 equivalent) was added. The reaction mixture was cooled to lick it. Diethylhydrazine hydride sodium hydride (178 mg, 840 μιηοΐ, 1.5 eq.) was added. The reaction mixture was dropped for 2 hours at the temperature. The reaction was poured into water and then saturated NaHC03 was added to the solution until it was basic. The solution was extracted twice with EtOAc (EtOAc)EtOAc. The solid was triturated with diethyl ether to give 6-gas-4-(5-(1-ethylpiperidin-4-yl)bipyridin-2-ylamino)-2-methylpyridazine-3 (2H )-ketone (121 mg '62%). Observed by LC/MS-ESI [M+H]+ 348. Step 2. '6-Chloro-4-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-2-methylpyridazine_3 (2H) in a 50 mL tube )-ketone (121 mg, 348 μηιο 1.00 equivalent) and (2-(ethyloxyindenyl)_3_(6_t-butyl-8-fluoro-indole-side oxime 秦0- 2 (1) Η)-yl)phenyl) tri-gas dechlorination (165 mg, 348 μηιοί, 1.00 when 157475.doc • 197·201211039 amount) combined with BuOH (4 ml) gave an orange solution. Add water (l.oo ml). X-PHOS (16.6 mg ' 34.8 μηιοί, 〇.1 eq.) and tripotassium wall silicate (148 mg ‘ 696 μιηοΐ ' 2 equivalents) were added. Bis(diphenylpyridinone)palladium (10.0. mg ' 17.4 μπιοί ' 0.05 equivalent) was added. The reaction mixture was purged with argon. The mixture was heated in an oil bath at 100 ° C for 1.5 hours and then cooled to room temperature. The reaction mixture was poured into 75 mL H20 and EtOAc EtOAc. The organic layers were combined and dried over Na2SO4. Concentrate in vacuo. The crude material was purified by flash chromatography (EtOAc:EtOAc:EtOAc The solid was wet-milled with Et20 to give 2-(6-t-butyl-8-fluoro-1-oxooxypyridinium-2(1H)-yl)-6-(5-(5-(1-) Ethyl 0 bottom bite - 4 - base) π ratio ° - 2 -aminoamino)-1-indolyl-6-sideoxy-1,6-dihydrod-zhen-3-yl)phenylhydrazine Purpose (147 mg, 62%). Observed by LC/MS-ESI [M+H]+ 680. Step 3. To 2-(6-t-butyl-8-fluoro-1-o-oxo-oxazine-2(1H)-yl)-6-(5-(5-(1-ethyl)定β-yl) 比-2-ylamino)-1-indolyl-6-o-oxy-1,6-dihydropyridazin-3-yl)benzyl ester (147 mg, Potassium carbonate (59.8 mg, 432 μιηοΐ, 2.0 eq.) was added to 216 μπιοί, 1.00 eq. The reaction mixture was stirred at 40 ° C for 1 hour. Cool the solution to room temperature. Concentrate in vacuo. The residue was dissolved in DCM / water and the layers were separated. The aqueous layer was extracted once with DCM. The organic layers were combined and dried over Na 2 SO 4 . Concentrate in vacuo. The crude material was purified by flash chromatography (EtOAc, EtOAc (EtOAc: EtOAc: EtOAc: EtOAc) -[5-(1'-ethyl-1',2',3,4,5,6,-hexahydro-157475.doc •198- 201211039 [3,4"bipyridin-6-yl Amino)-1-methyl-6-tertiaryoxy-1,6-dihydro-pyridazin-3-yl]-2-pyridyl-phenyl}-8-fluoro-2H-0-t-butyl- 1-ketone (108 mg, 78%). Observed by LC/MS-ESI [M+H]+ 638. NMR (300 MHz, chloroform-d) δ ppm 1.16 (br. s., 2 H) 1.43 (s, 9 H) 1.84 (br. s.5 4 H) 2.06 (br. s., 2 H) 2.51 ( Br. s·,3 H) 3.11 (br. s·,2 H) 3.69-4.09 (multiple peaks and overlapping single peaks, 4 H) 4.42 (d, /=6.80 Hz, 2 H) 6.91 (d, /= 8.69 Hz, 1 H) 7.37-7.77 (m, 6 H) 8.11-8.36 (m, 3 H) 8.60 (s, 1 H) Preparation 1-31 Example 31 6-Ter Butyl-2-{3-[ 5-(l,5-Dimethyl-1H-pyrazol-3-ylamino)-1-indolyl-6-yloxy-1,6-dihydro-pyridazin-3-yl]-2 -Hydroxymethyl-phenyl}-8-fluoro-2H-blown. Qin-1-one

Step 1. 1,5-Dimethyl-1H-pyrazol-3-amine (4 〇〇 mg, 3.6 mmol, 1.00 eq.) and 4-bromo-6-chloro-2-methylpyridazine _3 ( 2H)-ketone (965 mg, 4.32 mmo, 1.20 equivalents) with 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (312 mg, 540 μηιοί, 〇_ 15 equivalents), carbonic acid planer (3.52 g, 10.8 mmol, 3 equivalents) and ginseng (diphenylmethyleneacetone) dipalladium (〇) (165 mg, 180 μιηοΐ '0.05 equivalent) of dioxane (1 〇) .〇ml) combination. The solution of 157475.doc -199· 201211039 was degassed with Ar. The reaction mixture was heated at EtOAc (18 mL). The mixture was cooled to room temperature. The mixture was diluted with 100 ml of DCM. The organic layer was washed with water. The organic layer was dried over EtOAc EtOAc. '40 g, 10% to 5〇% (6〇:1〇:1 DCM: MeOH:NH4OH)/DCM gradient) Purification of crude material to give 6-gas-4-(1,5-dimercapto-1H- Pyrazol-3-ylamino)-2-methylpyridazine_3(2H)-one (408 mg, 45%). LC/MS-ESI observed [M+H] + 23 5 » Step 2. In a 50 mL tube, 6-gas-4-(1,5-dimethyl-1Η-pyrazol-3-ylamino)-2-methylindol-3(2Η)-one (1〇) 〇mg, 394 μιηοΐ, 1.00 equivalents) and (2-(ethyloxyindenyl)-3-(6-tert-butyl-8-fluoro-1-o-oxypyridazine-2(1 Η)- Base phenyl) succinic acid (224 mg, 473 μηηοΐ, 1.2 eq.) combined with BuOH (4.00 ml) to give an orange solution. Add water (丨0〇ml). Add X-PHOS (l 8.8 mg ' 39.4 Ηηιοί, 0.1 eq.) and tripotassium citrate (167 mg ' 788 μιηοο 2 equivalent). Add bis(diphenylarbenium acetal)! Bar (11.3 mg, 19.7 μιηοΐ, 0.05 eq) Purify the reaction mixture with argon. Warm the solution in an oil bath for 1.5 hours at 100 ° C. The solution was allowed to cool to room temperature. The reaction mixture was poured into 75 mL KhO and extracted with DCM. The crude material was purified by flash chromatography (25 g, EtOAc: EtOAc: EtOAc: EtOAc: EtOAc) The ratio of 2-(6-t-butyl-8-fluoro-1-o-oxoxime-2(111)-yl)-6-(5-(1,5-dimercapto-1) was obtained. 3-Ominoamino)-1-indolyl-6-oxo-1,6-dihydrodazin-3-yl)benzyl ester (186 mg, 81%). LC/MS-ESI observation Value [M+H]+ 586. 157475.doc • 200· 201211039 Step 3. To 2-(6-t-butyl-8-fluoro-1-oxophthalazine-2(1H)-yl acetate -6-(5-(1,5-dimercapto-1H-pyrazol-3-ylamino)-1-indolyl-6-yloxy-i,6-dihydropyridazine-3- Potassium carbonate (87.8 mg, 635 μιηοο 2.0 eq) was added to benzyl (1 00 mg, 318 mM ΐ ΐ, 1.00 eq.) MeOH (15.0 ml). The reaction mixture was stirred at 40 ° C for 2 hours. Cool the solution to room temperature. Concentrate in vacuo. The residue was dissolved in DCM / water. Separate the layers. The aqueous layer was extracted once with DCM. The organic layers were combined and dried over Na 2 SO 4 . Concentrate in vacuo. The crude material was purified by flash chromatography (12 g, 0% to 35% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to afford 6-t-butyl-2-{3 -[5-(l,5-dimethyl-1H-0 is 0--3-amino-amino)_ι_methyl-6-o-oxy-1,6-dihydro-pyridazin-3-yl] 2-Hydroxymethyl-stupyl 8_fluoro-2H-phthalazin-1-one (75 mg '44%). Observed by LC/MS-ESI [m+H]+ 544. 4 NMR (300 MHz, chloroform - &lt;i) δ ppm 1.43 (s,9 Η) 2·28 (s, 3 Η) 3.75 (s, 3 Η) 3.88 (s, 3 Η) 4.40 (s, 2 Η) 5.92 (s, 1 Η) 7.41-7.60 (m, 4 Η) 7.62-7.69 (m, 1 Η) 7.78 (s, 1 Η) 7.96 ( s, 1 Η) 8.29 (d, /=2.64 Hz, 1 Η) Preparation 1-32 Example 32 6-Terbutyl-8-fluoro-2-(2-hydroxymethylmethyl-5-[5- ((S)-l_methyl-° ratio 17 each -3-yl)-1! than 11-denylamino]-6-sideoxy-1,6-dihydro-indole. Qin -3-yl}-phenyl)-2H-phthalazin-1-one 157475.doc -201- 201211039

Step 1. Treatment of 3-sided oxygen with THF (25.2 ml, 25.2 mmol, 1.07 equivalents) containing 1 μ bis (tridecyldecylalkyl) aminide in a 500 mL three-necked flask at -78 °C. A solution of the third butyl pyrrolidine-1-decanoate (4.5 g, 23.6 mmol, 1.00 equiv) in THF (180 mL). At _78. (After stirring for 15 minutes, a solution of hydrazine-phenyl bis(trifluoromethane) was added (i.2 g, 28.3 mmol, 1.20 eq.) in THF (60.0 ml). The mixture was warmed to room temperature. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The crude material was purified by chromatography (3 〇〇g, 〇% to 30% EtOAc in hexane) to give 3 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ T-butyl citrate (2.3 g, 31%). Step 2. In the 25 0 mL round bottom flask, '3- 3-gas oxime was burned to 醯oxy-2,5-dihydro--0 嘻-1 - formic acid dibutyl hydrazine (2.3 g ' 7.25 mmol, ΐ · 〇〇 equivalent) combined with THF (60 ml) to give a colorless solution. Purify the solution with argon for 1 min. Add potassium carbonate (5.06 g ' 36.2 mmol, 5.0 equivalents), 5 (4,4,5,5-tetradecyl-1,3,2-methoxystone _2. kibine bite 2_amine (1 91 g, 8.7 mmo, 1.20 equivalent) , 肆 (triphenylphosphine) put (0) (83 8 mg, 72 5 J57475.doc • 202· 201211 039 μηιοί, 〇_〇1 eq.) and water (1.2 ml). The reaction mixture was heated to 70 ° C and stirred for 16 hours. The reaction mixture was poured into saturated NaHC03 and extracted twice with EtOAc. Drying over Na2SO4, EtOAc (EtOAc m.) Tert-butyl 3-pyridin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.03 g, 54%). mp. 3. Dissolve 3-(6-aminopyridine-3-yl)_2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (1.5 g, 5.74 mmol, 1.00 equiv) in MeOH (60 ml The solution was purged with argon, then treated with palladium/activated carbon (Degussa) (611 mg, 57·4 μπι〇ι, 0.01 eq.). The suspension was purged with hydrogen' and stirred under a hydrogen atmosphere for 48 hours. The reaction mixture was filtered through a 45 μιη glass frit. The filtrate was concentrated in vacuo to give 3-(6-amine, mp. mp. The enantiomers were separated by palmitic SFC HpLC. Item

Preparative column. DAICEL AD 2x25 oven temperature: 40 ° C Conditioner: MEOH regulator % : 15 Flow rate: 70 mL Compound weight: 161 〇 mg

Solubility: Good solubility in MeOH Solubility: 4〇mg/mL Injection volume: 10 mg Injection volume: 0.3 Wavelength: 220 nM Collection method: Forced time window Cycle time: 6 minutes Column times: 16ι 157475.doc 201211039 Obtained (S )_3-(6-Amino-0-bite-3-yl)-°Bhabite-1-carboxylic acid tert-butyl vinegar (307 mg' 20%) and (R)-3-(6-amino group- 0 to 0 -3-yl)-0 piroxicam _ι·carboxylic acid tert-butyl ester (399 mg, 26%) enantiomer. For the two enantiomers, LC/MS-ESI observed [M+H] + 264. Step 4 · (S)-3-(6-Aminopyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (307 mg ' 1.17 mmol '1.00 equivalent) and 4-bromo-6-gas- 2-methyl. Rhizalazine_3(211)-ketone (313 mg' 1.4 mmol' 1.20 equivalent) and 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzophenanthine (1〇) 1|11§, 175 0111〇1, 〇.15 equivalents), carbon brewing (1.14 g, 3.5 mmol, 3 equivalents) and ginseng (diphenylarbenium acetonide) gemini (0) (53.4 mg ' 58.3 μιηοΐ , 0.05 equivalents of dioxane (8.0 ml) combination. The solution was degassed with Ar. The reaction mixture was heated at 1 ° C for 8 hours. The solution was cooled to room temperature and diluted with 1 mL of DCM. The organic layer was washed with water and then dried over a MgSCU. Concentrate in vacuo. Purification of the crude material by flash chromatography (EtOAc, 24 g &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&& Oxyl-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (456 mg, 96%). Observed by LC/MS-ESI [M+H]+ 405. Step 5. (S)-3-(6-(6-Ga-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino). -base). Pyrrolidine tributyl methacrylate (456 mg ' 1.12 mmol '1.00 equivalent) was dissolved in a mixture of citric acid (2 〇〇 and 37 〇 / furfural (4 〇 ml). Stirring at 70 ° C The mixture was stirred for 18 hours. The solution was cooled to room temperature and water was added. The aqueous solution was extracted once with DCM. The aqueous layer was taken to pH = 14 with solid K2C03 157 475. doc s. 204-201211039. A solid was formed and filtered to give (S)-6 -Ga-2-methyl-4-(5-(1-decylpyrrolidin-3-yl)pyridine, 2-ylamino)pyridazine-3(2H)-one (408 mg ' quantitative yield LC/MS-ESI observation [M+H]+ 320. Step 6. In a 50 mL tube, (S)-6-chloro-2-methyl-4-(5-(1-indolyl) Pyrrrolidin-3-yl)pyridin-2-ylamino)pyridazine_3(2H)-one (100 mg, 313 μιηοΐ ' 1.00 equivalent) and (2-(ethyloxymethyl)-3-() 6-Tertibutyl-8-fluoro-1-oxooxazin-2(1 Η)-yl)phenyl)trifluoroborate (163 mg &gt; 344 μιηοο 1.1 equivalent) and BuOH (4.0 ml Combine to give an orange solution. Add water (1.0 ml), add X-PHOS (14.9 mg, 31.3 μιηοΐ, 0.10 罝) and add acid (133 mg, 625 μηιοί 2.0 eq.) Add bis(diphenylarhenylidene) 1 bar (8.99 mg, 15.6 μηιοί, 0.05 eq.). Purify the reaction mixture with argon, then heat at 18 ° C in an oil bath. The reaction mixture was cooled to room temperature, then poured with EtOAc EtOAc (EtOAc)EtOAc. g, 50% to 100% (60:10:1 DCM: MeOH: NH4OH) / DCM gradient) purified crude material to give acetic acid (S)-2-(6-t-butyl-8-fluoro-1- side Oxypyridazine-2(1H)-yl)-6-(1-indolyl-5-(5-(1-methyl) than σ-decyl-3-yl). 6-o-oxy-1,6-dihydropyridazin-3-yl)benzyl ester and 6-t-butyl-8-fluoro-2-(2-hydroxyindenyl-3-{1 -methyl-5-[5-((S)-l-fluorenyl-pyrrolidin-3-yl)-.pyridin-2-ylamino]-6-o-oxy-1,6-dihydro a mixture of pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one (105 mg total, 52%). LC/MS-ESI observed [M+H]+ 652 and 610. 157475.doc -205- 201211039 Step 7. To (3)-2-(6-t-butyl-8-fluoro-1-oxo-oxazine-(111)-yl)-6-(1) -methyl-5-(5-(1-F-pyridolidin-3-yl)pyridin-2-ylamino)-6-o-oxy-1,6-dihydropyridazin-3-yl)phenylhydrazine Ester with 6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3-{l-methyl-5-[5-((S)-l-methyl-pyrrolidin-3- ))-pyridin-2-ylamino]-6-o-oxy-1,6-diaza-healo 11-heptyl-3-yl}-phenyl)-2H-°太嘻-1-嗣 (105 mg Carbonate (44.5 mg, 322 μιηοΐ '2.0 equivalent) was added to a mixture of MeOH (10 ml). At 4 〇. The reaction mixture was stirred for 1.5 hours. The mixture was cooled to room temperature and the layers were separated by dilution with DCM / water. The aqueous layer was extracted once with DCM. The organic layers were combined and dried over Na 2 EtOAc. Concentrate in vacuo. The resulting solid was wet-milled with EhO to give 6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3-{l-fluorenyl-yl-. 嘻 定 -3-yl)-° Ratio of β-1,4-aminoamino]-6-sideoxy-dihydro-哒

°Qin-3-phenylene)-2Η-° too α Qin-1-嗣 (80 mg ‘ 81%). The lc/MS-ESI observation [Μ+Η]+ 610.1 NMR (in CDC13) was consistent with the desired product. Preparation 1-33 Example 33 6-Second-butyl-8-fluoro-2-(2-carbosyl-3-{1-罗基-5-[5~((汉)_1_methyl_ ° ratio洛--3-yl)-bite-2-ylamino]-6-sideoxy-1,6-dihydromethylphenyl}-phenyl)-2Η-pyridazine-1-_ 157475.doc - 206- 201211039

Step 1. This reaction was carried out under conditions similar to those described in Step 4 of Preparation Example 32 above. (R)-3-(6-(6-Gaxo-2-indolyl-3-oxo-2,3-dihydroethyl)&gt;Qin-4-ylamino)pyridin-3-yl)pyrrole Butyl-l-decanoic acid tert-butyl ester (555 mg, 90%). Observed by LC/MS-ESI [M+H]+ 405. Step 2. This reaction was carried out under conditions similar to those described in Step 5 of Preparation Example 32 above. (R)-6-Ga-2-indolyl-4-(5-(1-methyl&lt;»比略____)) than biting _ 2-ylamino) 哒嗓-3 (2H )-ketone (807 mg 'quantitative) ° LC/MS-ESI observed [M+H]+ 320. Step 3.

This reaction was carried out under conditions similar to those described in Step 6 of Preparation Example 32 above to give acetic acid (R)-2-(6-tert-butyl-8-fluoro-1-oxoxypyridazine-2 (1H)-yl)-6-(1-indolyl-5-(5-(1-indolyl) piroxime-3-yl) anthracene ratio _2_ylamino)-6-side oxygen Base-1,6-dihydrodazin-3-yl) awkward | with 6-t-butyl-3-8-fluoro-2-(2-hydroxyindol-3-{1·methyl-5-[ 5-((R)-l-methyl-pyrrolidinyl-3-yl)- 0-dodec-2-ylamino]-6-oxo-oxy-1,6-dihydro-adazin-3- Mixture of base _ phenyl) _2h_ 0 oxazol-1-one (total 135 mg' total 66°/〇p LC/MS-ESI 157475.doc -207- 201211039 Observations [M+H]+ 652 and 610 Step 4. The reaction was carried out under conditions similar to those described in Step 7 of Preparation Example 32 above. 6-T-butyl-8-fluoro-2-(2-hydroxydecyl-3-{l- Methyl-5-[5-((R)-l-methyl-pyrrolidin-3-yl)-pyridin-2-ylamino]_6_sideoxy-1,6-dihydro-pyridazine- 3-Methyl}-phenyl)-2H-tol-1-one (124 mg, 98%). mp.m.m. Consistent. Preparation 1-34 Step 1. Preparation of 4-mercaptosuccinyl-3,4,5,6-tetrahydro-2Η- [1,2·]

Under argon, add bromonitro" to the 15 mL argon-dried microwave reaction vial (300 mg ' 1.47 mmoL, 1.00 equivalent) and K2C 〇 3 (264 mg, 1.91 mm 〇L, 1.3 eq.) 'Get a pale yellow slurry. N-indenyl sulphate (192 mg '212 μΐ ' ι·9 ΐ mmol, ι·3 equivalent) was added dropwise, and the reaction mixture became a thick orange-yellow slurry. Heat in an oil bath to 7 (rc, dilute with dioxane (10 mL) and elute with DCM (10 mL) to dry to give a yellow solid for 1.5 s. then stirred overnight at room temperature. The mixture was transferred through a fritted funnel and used to dilute. The combined filtrate and washings were concentrated to dry 157 475. doc - 208* 201211039 (328 mg 'yield 89%) which was used directly in the next step. Preparation of 4_mercapto-3,4,5,6-tetrahydro-2Η-[1,2,]bipyrazin-5'-ylamine

2-(4-Mercaptopiperazin-1-yl)-5-nitropyrazine (328) at temperatures

The mg ' 1.47 mmol) was dissolved in MeOH (15 ml). Pd/C (1% by weight) (50 mg) was added while stirring the reaction mixture. The reaction mixture was placed under a Ha balloon and stirred at room temperature for 15 hours. The reaction mixture was filtered through celite and washed with MeOH (30 mL). The filtrate was stripped and dried under vacuum, then azeotroped twice with toluene to give a pale brown gum (280 mg, yield 89%). Step 3. Preparation of 6-chloro-2-indenyl_4_(4_mercapto-3,4,5,6-tetrahydro-2H-[1,2']bipyrazin-5'-ylamino) -2H-pyridazine-3·one

Add aminopyrazine (280 mg, 1.45 mm 〇1, i 〇〇 equivalent) to a 15 mL microwave reaction vial (heat and argon drying) 157475.doc •209· 201211039 under argon bubbling A solution of oxane (7 ml). To this solution, bromosinone (421, 1.88 mmo, 1.3 equivalents), CS2C03 (1.3 g, 3 99 lysine 2,75 equivalents), xantphos (126 mg, 217 μηιο 〇·15 equivalents), and double (Diphenylarbenium acetonide) palladium (62.5 11^'109 4111〇1, 〇_〇75 equivalent). The reactant was sealed and heated in an oil bath at 10 ° C (bath temperature) for 7 hours, followed by stirring at room temperature overnight. The reaction was filtered through a sintered funnel and washed with EtOAc (2 mL). The combined filtrate and washings were concentrated to dryness. The residue was taken up in 10 mL / EtOAc EtOAc (EtOAc) Yellow solid. Example 34 Step 4. Preparation of 6-t-butyl-8-fluoro-2-{2-hydroxymethyl-3-[l-fluorenyl-5-(4-methyl-3,4,5,6- Tetrahydro-2H-[1,2']bipyrazin-5,-ylamino)-6-o-oxy-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H- Pyridazine-1-one

157475.doc •210· 201211039 Adding 6_gas_2_methyl_4_(4_曱美3,4,5,6-tetrahydro-2H-[1,2'] to a 15 mL microwave reaction flask Dipyridazine _5, _ ylamino) 2H-pyridazinone (η mg, Chuan μηιοί ' 1.00 equivalent) of 7 red n-butanol and 丨 * machine water. Argon was bubbled through the suspension. (2_(Ethyloxymethyl)-3-(6-tert-butyl_8_fluoro_丨_ oxaoxypyridazine-2(ιη)_ base) was added sequentially to the slurry under stirring. Phenyl) potassium trifluoroborate (149 mg, 211 μηι〇1, 丨〇〇 equivalent), ^ PHOS (15.1 mg, 31.7 μηιοb 0.15 equivalent). To this mixture was added bis(diphenylmethylenepropene)palladium (9.12 mg, 15.9 μιηοΐ, 〇.075 when ® amount). The tube was sealed and heated at 110 ° C (bath temperature) for 3 hours, then cooled to warm. A solution of NaOH (84 mg ' 2.11 mmol, 1 eq.) in water (1⁄4 mL) was added and the mixture was stirred for 3d. The layers were separated and the aqueous layer was extracted with EtOAc and combined with previous organic layers. The combined extracts were concentrated to 4-5 mL. Purification of the crude material by preparative TLC (11 X) with 1% (1% EtOAc / EtOAc) Light yellow solid. ]^: 235-24 (TC. 丨11 NMR (300 MHz, chloroform-A i.43 (s, 9 H), 2.36 (s, 3 Η), 2.51 (t, J = 5.0 Hz, 4 H), 3.50 (t, /=5.0 Hz, 4 H), 3.90 (s, 3 H), 3.95 (t, /=6.2 Hz, 1H), 4.40 (d, J=6.2 Hz, 2H), 7.43-7.65 (m , 5 H), 7.88 (d, /=1.13 Hz, 1 H), 8.03 (d, «7=1.51 Hz, 1 H), 8.15 (s, 1 H), 8.25 (s, 1H), 8.30 (d &lt;7=2.5, 1 H) LCMS (ES): 626 (M+H), RT = 1.94 min. Preparation 1-35 Step 1. 157475.doc -211 - 201211039 Preparation (5-cyclobutylamine Methyl _. than 嘻_2-yl)·aminobutyric acid tert-butyl ester

To a dried 1 〇〇 mL round bottom flask was added cyclobutylamine (740 mg, 889 μΐ ' 10.4 mmol, 3 eq.), K 2 CO 3 (480 mg ' 3 · 47 mmol ' at room temperature under argon. 1.00 equivalents) and THF. To the mixture was added dropwise a solution of (5-methanol-β-pyridyl-2-yl)-aminocarboxylic acid terpene vinegar (1 g, 3-47 mmol, 1.00 eq.) in THF. The resulting reaction mixture was vigorously stirred at room temperature under argon overnight. The reaction was concentrated, diluted with water / DCM elut The combined organic extracts were concentrated to give a solid. The crude product was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut The title compound. Step 2. Preparation of 5-cyclobutylaminomethylpyrazine-2-ylamine

'5-((cyclobutylamino)methyl)pyrazine-2-ylamine 157475.doc -212· 201211039 carboxylic acid third butyl vinegar (10) is called '...(4)^(10) in a 15 mL microwave tube The mixture was dissolved in 2,2,2-^6^ (119 mg. 12 ml, M9 mm 〇1, 1. 〇〇 ft), and the mixture was heated in a sealed tube for 3 hours under HOt. The crude reaction mixture was concentrated in vacuo, and was re-concentrated to remove residual tri-Iethanol to give the material to toluene to give 2 mg (95%) of the title compound. Step 3.

Preparation of 6-gas-4-(5-cyclobutylaminomethyl·D-pyridin-2-ylamino)_2-methyl 2H-pyridazin-3-one

Add 5-((cyclobutylamino)indolyl)pyrazin-2-amine (280 mg, 1.57 mm〇b 1 〇〇 equivalent) to dioxane to a 15 mL microwave reaction vial under argon bubbling Solution in (7 ml). To this solution was added 4_bromo-6-chloro-2-indolin-3-(2H)-one (456 mg, 2.04 mmol '1.3 equivalent), Cs2C03 (1.3 笆 '3.99 111111 2.5 2.54 equivalent) 1 Coffee 1) 11 〇 8 (136 111 邑, 236 0111 〇 〇, 15 equivalents) and bis (diphenylidene acetonide) palladium (67 7 mg, 118 μηη〇ι, 0.075 equivalent) sealed reaction tube, and It was heated in an oil bath at 1 Torr 5 (bath temperature) for 7 hours, followed by stirring at room temperature overnight. The crude reaction mixture was filtered and washed with EtOAc (EtOAc) The filtrate and washing solution combined with 157475.doc -213-201211039 were concentrated and adsorbed onto the silicone. The mixture was purified by EtOAc (EtOAc) (EtOAc) eluting 39%) title compound. Example 35 Step 4. Preparation of 6-t-butyl-2-{3-[5·(5-cyclobutylaminoindolyl)-pyrazine-2-ylamino)-1-indenyl-6- Sideoxy-1,6-dihydro-indole _3_yl] via methyl-phenyl}-8-fluoro-2Η-pyrazin-1-one

Add 6-gas_4_(5-cyclobutylaminoindolyl-0-pyridyl-2-ylamino)-2-methyl-2H-pyridazin-3-one to a 15 mL microwave reaction vial (71 mg, 221 μιηοΐ '1.00 equivalent) of 7 mL of n-butanol and 1.4 mL of water. Argon was bubbled through the reaction mixture. 2-(6-Tert-butyl-8-fluoro-1-o-oxy-1H-pyridazin-2-yl)-6-(4,4,5,5-tetraacetic acid) was added to the reaction. Methyl-[1,3,2] dioxaborom-2-yl)-azain (218 mg, 309 μιηοο 1.39 eq.), tripotassium phosphate (103 mg, 487 μιηοΐ), X-PHOS (15.8) Mg, 33.2 μπιοί, 0·1 5 equivalents). The mixture was purged with argon, and (diphenylmethyleneacetone) was added (9.55 mg, 16.6 μιηο, 0.075 eq.). The tube was sealed and heated at 110 ° C (bath temperature) for 3 hours. The reaction mixture was cooled to room 157475.doc - 214 - 201211039 A solution of NaOH (189 mg) in water (1.5 mL) was added and the mixture was stirred at 37 ° C for 3 hours in an oil bath. The crude reaction mixture was diluted with water (1 mL) and extracted with dichloromethane (3×1 mL). Concentrate the organic phase and use 5-10. /. (1/1) EtOAc/n-heptane was dissolved in EtOAc/n-heptane to afford purified solvent (light yellow) and mixed solvent (yellow). The pure soluble fraction was concentrated and dissolved in DCM. Methanol was added to make a solvent mixture of 1% MeOH in DCM and heptane was added to allow the solid to stand out immediately. The suspension was allowed to stand at room temperature overnight, and the obtained solid was filtered and washed with n-heptane and dried to give the title compound: mp: 163-167 ° C. (300 MHz, gas-like-J) 1.43 (s, 9 H), 1.70- 1.72 (m, 4H), 2.19-2.22 (m, 2 Η), 3.28-3.31 (m, 1Η), 3.75 (t, J =6.2 Hz, 1H), 3.80 (s, 2H), 3.89 (s, 3H), 4.40 (d, J=6.2 Hz, 2H), 7.43-7.65 (m, 5 H), 8.28 (d, J=1.13 Hz, 1 H) , 8.30 (d, J=2.5, 1 H), 8.36 (d, J=1.51 Hz, 1 H), 8.40 (s, 1 H), 8.60 (s, 1H). LCMS(ES) : 611 (M+H), RT = 2.511 min. Preparation 1-36 Step 1. * Preparation of monomethyl-[2-(5-Shosyl-n-pyrazine-2-yloxy)-ethyl]-amine

157475.doc 215- 201211039 To 100 ml of the dried round bottom flask was added bromonitropyrazine (300 mg, 1.47 mmo 1.00 eq.) and CH3CN (10 ml). Under argon, Κ2〇〇3 (203 mg, 1.47 mmol, 1.00 eq.) was added to the mixture to give a pale yellow syrup. To the syrup, N,N-didecylaminoethanol (131 mg' 148 μM, 1.47 mmol, 1.00 equivalent) was added dropwise. The reaction turned into an orange slurry&apos; and it was stirred overnight at room temperature. The reaction mixture was filtered and washed with CH3CN (3×20 mL). The combined liquid and washings were concentrated in vacuo and purified by column chromatography eluting with 5-10% (1% EtOAc/H. This gave 270 mg (87%) of the title compound. Step 2. Preparation of 5-(2-dimethylamino-ethoxy)-.嗓_2-ylamine

Add Me to a 5 〇〇 round bottom flask containing hydrazine, hydrazine dimethyl-2-(5-nitro"pyridyloxy)ethylamine (27 〇 mg, U mm 〇 1, L00 equivalent) 〇H (2〇mi) and 丨0% Pd/C (6〇mg). The reaction was stirred under a hydrogen atmosphere for 2 hours' followed by storage for 3 days. The celite was passed through a mixture of EtOAc (EtOAc m.). (2-Dimethylamino-ethoxybisazin-2-ylamino)-2-157475.doc •216- 201211039 Mercapto-2H-pyridazin-3-one

Add 5-(2-(dimethylamino)ethoxy)pyrazin-2-amine (190 mg, 1.04 mmo 1.00 eq.) to dioxane in a 15 mL microwave reaction vial under argon ( Solution in 7 ml). Add 4-bromo-6-gas-2-mercaptopyridazine-3(2H)-one (303 mg, 1.36 mmol '1.3 eq), Cs2CO3 (1.02 g, 3.13 mmol, 3 equivalents), xantphos (90.5 mg, 156 μηιοί, 0.15 eq.) and bis(dibenzylideneacetone)palladium (45.0 mg, 78.2 μπιοί, 0.075 eq.)' and the reaction tube was heated in an oil bath at 10 ° C (bath temperature) for 7 hours. The mixture was then filtered overnight at room temperature and the solid was washed with dioxin (2 mL) and DCM (5 mL). The combined filtrate and washings were concentrated. By using 〇-1〇〇/. (1/1) EtOAc/Heptane (EtOAc) elute Example 36 Step 4. Preparation of 6-t-butyl.2_(3_{5_[5_(2.dimethylamino)-ethoxy)-.pyrazine-2-ylamino]-1-indenyl 6_Sideoxy_U6_Dihydro-pyridazine_3_Kibu 2_hydroxymethyl-phenyl)-8-gas-2H-pyrazine-1-_ 157475.doc • 217- 201211039

Add 6-chloro- 4-[5-(2-dimethylamino-ethoxy)-pyrazin-2-ylamino-2-bromo-2-H-pyridazine to a 15 mL microwave reaction vial 3-ketone (89 mg, 274 μιηοΐ, 1.00 equivalent) of 7 mL of n-butanol and 1.4 mL of water. Add tripotassium phosphate (128 mg, 603 μηιοί), X-PHOS (19. 6 mg '41.1 μπι〇1, 0.15 equivalent) and 2-(6-tert-butyl acetate) to the solution under stirring and argon bubbling -8-fluoro-1-oxooxy 1 Η 呔 -2 -2 _ _ _ _ _ 6_(4,4,5,5-tetramethyl-[1,3,2]dioxaboran-2-yl) Benzyl methacrylate (279 mg, 395 μιηο Bu 1.44 eq.). To this mixture was added bis(dibenzylideneacetone)palladium (丨丨8 mg, 20.6 μπιοb 0.075 equivalent), and the reaction was heated at U (rc for 3 hours. Cooling the reaction to room temperature) and using NaOH (220 mg) was treated with a solution of water (1. 5 mL). The mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with EtOAc (50 mL) and water (50 mL). The organic phase was separated, washed with water (3 mL) and concentrated. The residue was purified by EtOAc/Hex (1%) eluted with EtOAc (EtOAc). The pure soluble fraction was concentrated and dissolved in DC crucible. The heptane was added to precipitate the product. The title compound was obtained as a white solid. Mp : ι85_ 190〇C. H NMR (300 MHz, gas-d-d) 1.43 (s, 9 H), 2.37 (s, 6 H) 2.74 (t, /=5.5 Hz, 2H), 3.85 (t, J=6.2 Hz, 1H) , 3.92 (s, 3H), 157475.doc -218- 201211039 4.40 (m, 4H), 7.43-7.65 (m, 5 H), 7.95 (d, J=1.13 Hz, 1 H), 8.06 (d, 7=1.51, 1 H), 8.26-8.35 (m, 3H). LCMS (ES): 615 (M+H). Example 37 Preparation of 6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3-{l-fluorenyl-5-[5-(4-methyl-piperazin-1-ylmethyl) )-[pyrazine-2-ylamino]-6-o-oxy-1,6-dihydro-pyridazin-3-yl}phenyl)-2H-phthalazin-1-one

Prepared by a procedure analogous to Example 35, but substituting decylpiperazine for the cyclobutylamine in Step 1, after LC chromatography and subsequent recrystallization from DCM/Heptane to afford 107 mg (53%) as a white solid. The title compound. ! ^··]. -218 ° C. H NMR (300 MHz, MV 1.43 (s, 9 H), 2.30 (s, 3 Η), 2.40-2.61 (m, 8H), 3.67 (s, 3H), 3.80 (t, J=6.2Hz, 1H ), 3.93 (s, 3H), 4.45 (d, /=6.2Hz, 2H), 7.43-7.65 (m, 5 H), 8.30 (d, J=2.5, 1 H), 8.33 (d, /=1.13 Hz, 1 H), 8.36 (d5 &gt; 1.51 Hz, 1 H), 8.43 (s, 1 H), 8.65 (s, 1H). LCMS (ES): 640 (M+H), RT = 2.104 min. Example 38 Preparation of 6-t-butyl-2-(3-{5-[5-(2-didecylamino-1,1-didecyl-ethoxybisazin-2-ylamino) -1-methyl-6-o-oxy-1,6-dihydro-pyridazine-3- 157475.doc -219· 201211039 keb 2-hydroxymethyl-phenyl)-8-fluoro-2H-indole Pyrazin-1-one

Prepared by a procedure similar to that of Example 36, but substituting the NN-dimercaptoaminoethanol of Step 1 with p-didecylamino-2-mercapto-propan-2-ol to give 100 mg (50 ° / 〇) ) title compound. Mp : 235-240 ° C. 'H NMR (300 MHz, chloroform-c〇1.43 (s, 9 H), 1.56 (s, 6H), 2.37 (s, 6H), 3.80 (t, J = 6.2 Hz, 1H), 3.90 (s, 3H ), 4.45 (d, 7=6.2 Hz, 2H), 7.43-7.65 (m, 5 H), 7.89 (d, J=1.13 Hz, 1 H), 7.96 (d, /=1.51 Hz, 1 H), 8.24 (s, 1 H), 8.30 (d, 7=2.5, 1 H), 8.35 (s, 1H) » LCMS (ES): 643 (M+H), RT=2.516 min. Preparation 1-39 Step 1 Preparation of [2-(6-bromo-pyridazin-3-yloxy)-2-methyl-propyl]-didecyl-amine

Add 1-(didecylamino)_2-mercaptopropan-2-ol (1.48 g ' 12.6 mmol '1.5 eq), THF and 3,6-dibromoindole (2 g) to a 100 mL round bottom flask , 157475.doc -220- 201211039 8.41 mmol, 1.00 equivalents of chilled flask to, then add NaH (572 mg 'l4.3mm 〇b 17 equivalents) in one portion. The turbid reaction mixture was allowed to warm to room temperature and at room temperature The resulting black reaction mixture was taken up in EtOAc (EtOAc m.) Step 2. Preparation of dibenzylidene-[6-(2-didecylamino)_ι,ι-dimethyl-ethoxy)-indol-3-yl]-amine

To a 15 ml microwave reaction vial was added 2-(6-bromopyridazin-3-yloxy)-N,N,2-tridecylpropanol-amine (5 mg, 1.82 mmol, 1.00 eq.) And benzene (7 ml). Air is bubbled through the mixture. To this mixture was added (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (170 mg, 274 μηιοί, 0.15 equivalent), Cs2C〇3 (2.38) g, 7.3 mmol, 4 eq.) and Pd(OAc) 2 (30.7 mg, 137 μιηοΐ, 0.075 eq.). At 120. (The reaction was heated in an oil bath for 7 h then stirred at rt overnight. EtOAc was evaporated from EtOAc EtOAc. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc. 2-Dimethylamino-1,1-dimethyl-ethoxy)-pyridazine_3_ylamine

N 〇, /

I To a 10 mL pear-shaped flask was added 6-(1-(didecylamino)-2-methylpropan-2-yloxy)-N-(diphenylhydrazinyl)pyridazine_3_amine ( 2〇〇mg, 534 μηιοί, 1.00 eq.) and MeOH (5.3 4 ml)» Add hydroxylamine hydrochloride (66·8 mg, 961 μπιοί, 1.8 equivalent) and sodium acetate (1〇5 mg, 1.28 mmol) to the mixture. '2.4 eq.) ^ The mixture was stirred at room temperature for 25 minutes, and the reaction mixture was adsorbed on a day of sulphur dioxide and 1/1 EtOAc/hexanes containing 〇_5% (MeOH containing 1% by weight of NH4OH). Dissolution was carried out by LC chromatography to purify 'yield 110 mg (98 ° / EtOAc). Step 4. Preparation of 6-chloro-4-[6-(2-dimethylamino]l5l-didecyl-ethoxy)-pyridazine-3-ylamino]-2-methyl-2H-indole Oxazin-3-one 157475.doc -222- 201211039

Add 6-(1-(dimethyl-n-hydroxy)-2-methylpropan-2-yloxy)pyridazin-3-amine (110 mg, to a 15 mL microwave reaction vial under a gas atmosphere). 523 μπΐ() 1, 1.00 equivalent) in dioxane (5 ml). To this solution was added 4_g-6-chloro-2-methylpyridazin-3(2H)-one (152 mg, 680 μιηοο 1.3 equivalent), Cs2C〇3 (511 mg, 1.57 mmol, 3 equivalents) , xantphos (45.4 mg, 78·5 μηιοί, 0.15 equivalent) and bis(dibenzylideneacetone)palladium (22.6 mg, 39.2 μιηοΐ '0.075 equivalent). The reaction tube was sealed and heated in an oil bath at 110 C (bath temperature) for 7 hours' then cooled to room temperature and stirred overnight. The reaction mixture was filtered and washed with EtOAc EtOAc. The combined effluent and washing liquid are concentrated in a vacuum. The reaction mixture was taken up in EtOAc (EtOAc) elute elute elute Example 39 Step 5. Preparation of 6-Secondyl-2-(2)(3_{5_[6-(2-didecylamino-didecyl-ethoxypyridazin-3-ylamino)-1.methyl -6-Sideoxy-1,6-dihydro-pyridazin-3-yl} 2 &amp; fluorenyl-benzyl)_8_fluoro_2}^_. Too 嗓_ι_ ketone 157475.doc -223 · 201211039

Add 6-gas-4-(6-(1-(dimethylamino)-2-mercaptopropen-2-yloxy)pyridazine_3_ylamino)_2 to a 15 mL microwave reaction vial Mercaptoazine _3 (2^[)-ketone (75 mg '213 μιηο 1.00 equivalent), n_Bu〇H (6 mi) and water (i. 5 ml). Addition of ethoxylated decyl-tert-butyl-8-fluoro-1-oxo-oxazine·2(1Η)-yl)phenyl)trifluoroborate (1〇1) to the mixture under argon Mg ' 213 μηιοί, 1.00 equivalent). Add x_pH〇s (1〇6 μ1, 31 9 μηιοί ' 0.15 eq.) and tripotassium phosphate (99 3 mg, 468 μηη〇ι, 2·2 eq.)' followed by the addition of bis(diphenylarhenylidene)palladium ( 91 7 mg, 15.9 μηιοί, 0.075 equivalent). The tube was sealed under argon and heated in an oil bath for 3 hours under U5t: then stirred overnight at room temperature. To this mixture was added 1 mL of distilled water containing 100 mg of NaOH. The mixture was warmed in an oil bath at 50 ° C for 3 hours, then stirred at room temperature overnight. The crude reaction mixture was diluted with water (2 mL EtOAc) The combined organic extracts were concentrated and adsorbed onto silica gel. The crude material was purified by chromatography eluting eluting eluting elut elut elut elut elut elut elut Title compound. MP: 140_145. (:4 NMR (300 MHz, gas-like i 43 (s, 9

H), 1.67 (s, 6H), 2.37 (s, 6H), 2.80 (s, 2H), 3.80 (t, J: 6.2 Hz, ih), 3.92 (s, 3H), 4.45 (d, J = 6.2 Hz, 2H), 6-90 (d, J 157475.doc -224- 201211039 -9 Hz, 1H), 7.10 (d, J=9 Hz, 1H), 7.43-7.65 (m, 5 Η), 8· 20 (s, 1 H), 8.28 (d, J=2.5, l H), 8.55 (s, lH) 〇 LCMS (ES): 643 (M+H), RT = 1.942 min. Preparation 1-40 Step 1. Preparation of 6-(1-mercapto-1,2,3,6-tetrahydro-pyridyl-4-yl)_da „秦_3_ylamine

Add tripotassium phosphate (143 g, 6 74 mmol), 6-bromopyridazin-3-amine (335 mg, 1.93 mmol) to a 15 mL microwave reaction vial, and vaporize 1-methyl-4-(4) ,4,5,5-tetradecyl_1,3,2-dioxaboron-2-yl)-1,2,3,6-tetrahydropyridinium (500 mg, 1.93 mmol), X_ph〇S (138 mg, 289 μηιοί) and bis (one sulfhydrylacetone) 7 mL of n-butanol (1.4 mg, 144 μιηοΐ) and 1.4 mL of H2 〇. The tube was sealed under argon and at 1丨5. The mixture was heated in an oil bath for 3 hours, then stirred at room temperature overnight. The phases were separated and the aqueous extracted with EtOAc (EtOAc) (EtOAc) The extract was combined with the EtOAc organic phase. The resulting solution was adsorbed onto silica gel and purified by LC chromatography eluting with 1:1 EtOAc/hexanes containing EtOAc/EtOAc (EtOAc: EtOAc/EtOAc) %) Title compound. Step 2. 157475.doc -225· 201211039 Equipped with 6-(1-methyl- 1 slightly; _4_yl)-pyridazine_3_ylamine

6-(1-Methyl-1,2,36-tetrahydropyridin-4-yl)pyridazine_3_amine (3 〇〇6, 1-58 〇1, I00 eq.) was dissolved in EtOH ( 30 ml). In a H_Cube apparatus (60 psi), the mixture was subjected to two cycles at room temperature in the presence of pd/c until the reaction was completed as determined by tlc. The solvent was removed in vacuo. Mg (89%) of the title compound. Step 3. Preparation of 6-gas "2-indolyl_4-[6-(1-methyl-piperidin-4-yl)-pyridazine-3-ylamino]- 2H-pyridazin-3-one

To a 15 mL reaction vial was added a solution of 6-(1-methylpiperidin-4-yl)pyridazin-3-amine (190 mg </ </ RTI> 988 </ RTI> </ RTI> 1.00 eq.) in dioxane (7 ml). Argon was bubbled through the solution and 6-chloro-2-methyl-4-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)pyridazine_3 was added. (2H)-ketone (160 mg, 430 157475.doc -226· 201211039 μιηοΐ, yield 43.5%) and Cs2C03 (966 mg, 2.96 mmol, 3 eq.). To this mixture was added xantphos (86 mg, 148 μιηοΐ, 0.15 S) and bis (one methylene acetone) (42.61118, 74.14111〇1, 0.075 equivalent). The tube was sealed under argon and heated in an oil bath at u 51 (bath) for 7 hours, then stirred at room temperature overnight. The reaction was diluted with EtOAc (1 mL). The combined washes were concentrated and purified by loading <RTI ID=0.0></RTI> to </RTI> <RTI ID=0.0> %) The title compound as an orange solid. Example 40 Step 3. Preparation of 6-t-butyl-8-fluoro-2-(2- mercapto-3-{l-methyl-5-[6-(l-methyl-piperidin-4-) ))-pyridazin-3-ylamino]-6-o-oxy-1,6-dihydro-indole. Qin_3_yl}-phenyl)-2H-phthalazin-1-one

Add 6-gas-2-mercapto-4-(6-(1-indolyl) to 4-ylamino) to a 15 mL microwave reaction vial (2H) )-ketone (160 mg, 478 μιηοΐ ' 1.00 equivalent), (2-(ethyloxyindenyl)-3-(6-tert-butyl-8-fluoro-1-o-oxypyridazine-2 ( 1Η)-Phenyl)phenyl)trifluoroborate (272 mg, 573 157475.doc -227 - 201211039 μιηο 1.2 equivalent) with n_Bu〇H (7 $ ml) and water (15 ml). Argon was bubbled through the solution for 5 minutes. X-PHOS (34.2 mg, 71,7 μΐΏο1 '0.15 equivalent) and tripotassium phosphate (304 mg, 1.43 mmol, 3 eq.) were added to the mixture, and argon gas was bubbled through the mixture for 5 minutes. To this mixture was added bis(monobenzylideneacetone)palladium (2〇6 mg, 35.8 μπιοί, 〇_〇75 equivalent). The tube was sealed under argon and at 1 Torr. The underarm was heated in an oil bath for 3 hours. The mixture was cooled to room temperature and treated dropwise with a solution of 220 mg NaOH in 1.5 mL water. The resulting mixture was heated in an oil bath at 5 ° C for 3 hours with vigorous stirring. The reaction mixture was diluted with water (20 mL) and EtOAc. The combined extracts were concentrated and loaded onto a 40 g tantalum tube column with 5-10% (containing 10% NH4OH)

Purified by EtOAc/EtOAc (EtOAc) elute Mp : 260-265 ° C. NMR (300 MHz, gas simulation - ώ〇 1.43 (s, 9 Η), 1.80-2.20 (m, 6H), 2.37 (s, 3H), 2.90-3.07 (m, 3H), 3.85 (t, J = 6.2 Hz, 1H), 3.92 (s, 3H), 4.45 (d, 7=6.2Ηζ, 2H), 7.15 (d, J = 9Hz, 1H), 7.35 (d, J=9Hz, 1H), 7.43-7.65 ( m, 5 H), 8.28 (d, 7=2.5, 1 H), 8.32 (s, 1 H), 8·78 (s, 1H). LCMS (ES): 625 (M+H), RT=2.21 Minute e preparation 1-41

Process G 157475.doc -228 - 201211039

Step 1. 1-(6-Gas-Acridine-3-ylindenyl)-4-mercapto-piperazine: 6-Chloronicotinaldehyde (10 μg '70.6 mmol, 1.00 equivalent) was suspended in 700 ml In DCM. Methyl 0 bottom oxime (8.84 g, 88.3 mmol, 1.25 eq.) and acetic acid (8.48 g, 8.09 m 141 mmol, 2.0 eq.) were added. Sodium triacetate borohydride (22.5 g, 1 〇 6 mmol, 1.5 eq.) was added portionwise over a few minutes. The reaction mixture was stirred at room temperature. There was no evidence of starting material after 3.5 hours. LCMS showed the product as well as a small amount of reduced starting material. Water, DCM were added sequentially, and the layers were separated. The layer was washed with saturated ammonium chloride, and the aqueous layer was combined with the initial aqueous layer to HM Na〇H to verify the aqueous extract. The aqueous layer was extracted 3 times with DCM, then dried and concentrated to give η Glucan yellowish oil (84.7%), which was used without further purification. Step 2. 5-(4-Methyl-pyrazine-ylmethyl) "Bit bite_2_ylamine: under nitrogen Add gas pyridinium-3-(ylmethyl)_4·f-piperazine (Μg'59_8 caffeine (10) equivalent), 2·(dicyclohexylphosphino), stupid (1) μ 157475.doc to the sealed tube. 229- 201211039 g, 12.0 mmol, 0.20 equivalent), ginseng (diphenylarbenium acetonide) _ dipalladium (0) (5.48 g, 5.98 mmo, 0.1 〇 equivalent), and 15 〇 ml ! 〇M double (three 曱Acrylating the solution of the clock in THF. Add 15 〇ml of thF » Degas the flask with argon. Cap the flask and heat the reaction vessel at 1 Torr. 3 M HC1 And DCM was added to the material and the layers were separated. The aqueous layer was basified with &lt;3&gt;M NaOH. The aqueous layer was then extracted three times with dc:m to give 3.2 g (2 5 · 9%) of yellow powder without further purification. That is to use. Step 3 6-Chloro-2-indolyl-4-[5-(4-indolyl-piperazinylfluorenyl)-pyridin-2-ylamino]-2H-pyridazin-3-one: under nitrogen, 5-((4-Methylpiperazinyl)indolyl)pyridin-2-amine (3.2 g, 15.5 mmol, 1.00 eq.), 4-bromo-6- ox-2-mercaptosin-3 (2H) Ketone (3.64 g, 16 3 mmol, 1.05 equivalent), xantphos (1.35 g, 2.33 mmo dip. 15 equivalents), ginseng (diphenylmethyleneacetone) dipalladium (0) (107 g, i 16 mm) 〇丨, 〇〇 75 equivalents) and carbonate planer (15.2 g, 46.5 mmo), 3.00 eq.) were added to a sealed tube. Dioxane (103 ml) was added and the solution was degassed with nitrogen. The mixture was heated overnight at 1 ίοc. The reaction mixture was filtered over celite, and the filter cake was washed with dcm. iM HCl was added and the layers were separated. Ffi2MNa 〇H basified aqueous layer and extracted several times with DCM. The residue was triturated with diethyl ether. The solid formed was filtered and dried to give 2 <RTI ID=0.0></RTI> </RTI> <RTIgt; Fluoryloxy-1H-pyridazin-2-yl)-6-{1-methyl-5-[5-('methyl-piperazin-1-yl-methyl)比 _2 _ _ 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 4-(5-((4-Methylpiperazin-1-yl)methyl)pyridin-2-ylamino)pyridazine-3(2H)-one (3.1 g, 8.89 mmol, 1.00 equiv), acetic acid 2-(6-tert-butyl_8_fluoro-indole-oxo-oxazine-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2 -Bismofluorene-2-yl)benzophenone (7.69 g ' 15.6 mmol, 1.75 eq.), x_ph〇s (424 mg, 0.89 mmol, 0.1 eq. equivalent), bis(dibenzylideneacetone) Palladium (255 mg, 0.44 mmol, 0.05 eq.) and tripotassium citrate (4.72 g, 22.2 mmol, 2.50 eq.) were added to a large microwave vial. The bottle was capped and purified. n-Butanol (3 5.5 ml) and water (9 ml) were added and the bottle was again purged and backfilled with nitrogen. The reaction was heated in a sand bath at 115 °C for 2.5 hours. Water and DCM were added to the reaction and the layers were separated. The organic layer was filtered through celite, concentrated, and purified by chromatography using DCM gradient from 0% to 25% methanol. The combined fractions with and without the protecting group were combined to give a combined yield of 4 · 5 g (about 74%). Example 41 Step 5. 6-Tertibutyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl) Methylpyridin-2-ylamino]]6_sideoxy-1,6-dihydro-pyridazine_3_yl}-phenyl)-2H-phthalazin-1-one: 2-(6) -Tertibutyl oxylHH oxazinyl)_6_ {1-mercapto-5-[5-(4-indolyl-piperazinyl]-indenyl)-. Amino]_6_sideoxy-1,6-hydrogen-pyridazine-3-ipylbenzoate (4.5 g, 6.61 mmol, i.oo equivalent) and potassium carbonate (1·37 g, 9.92 mmol, 1.50 equivalents) were dissolved in methanol and heated at 4 ° C for 1 hour. The reaction was cooled to room temperature and water was added dropwise 157475.doc • 231 - 201211039. The reaction was stirred overnight at room temperature. The solid which formed was washed with water and dried in a vacuum oven over a weekend to give 3.64 g (86.2%) of pale white crystalline solid. 1H NMR (300 MHz, DMSO-J6) δ ppm 9.39 (s,1 Η) 8.53 (s ,1 Η) 8.50 (d, J=2.3 Hz, 1 Η) 8.15 (d, *7=1.9 Hz, 1 h) 7.86 (d, "7=1.5 Hz, 1 H) 7_74 (dd, 7=13.4, 1.7 Hz, 1 H) 7.57-7.62 (m, 1 H) 7.50-7.57 (m, 2 H) 7.43-7.49 (m, 2 H) 4.52-4.61 (m , 1 H) 4.40 (br. s., 2 H) 3.77 (s, 3 H) 3.36 (s, 2H) 2.30 (br. s.5 8 H) 2.11 (s, 3 H) 1.37 (s, 9 H MS: (m+H)+=639. Preparation I-42 Example 42

Preparation of 6-t-butyl-8-fluoro-2-[2-hydroxyindolyl-3- using 2-methoxyethylamine in place of the methylpiperazine in step i using the general procedure described in Example 41 (5-{5-[(2-Methoxy-ethylamino)-methyl]-pyridin-2-ylamino}-1-methyl-6-yloxy-1,6-dihydrol - pyrazinyl)-phenyl]-2H-phthalazin-1-one. Prior to the second synthesis, the secondary amine was protected with a BOC group using standard procedures. In the next synthesis step of this compound, 1 M NaOH was used instead of potassium carbonate to remove the acetate protecting group, using THF as the solvent and at 157475.doc -232 - 201211039

Heat at 60 ° C for two hours, then stir at room temperature overnight. At the end of the synthesis, 'B〇c' was removed by heating the compound containing 1 1 i3,3,3-hexafluoro-2-propanol (using a large excess as a solvent) in a microwave for 3 Torr at 140 °C. Protection base. After purification by chromatography using a DCM gradient of 5% to 25% methanol, 75 mg of product was obtained as a yellow solid. Ifi NMR (300 MHz, DMSO-J6) δ ppm 9.37 (s,1 Η) 8.51-8.54 (m,2 Η) 8.20 (d, /=2.3 Hz, 1 H) 7.87 (s, 1 H) 7.75 (d , 7=14.4 Hz, 1 H) 7.64-7.69 (m, 1 H) 7.42-7.59 (m, 4 H) 4.57 (t, /=5.3 Hz, 1 H) 4.42 (br. s., 2 H) 3.77 (s,3 H) 3.61 (s,2 H) 3.37 (t, •/=5.7 Hz, 2 H) 3.21 (s,3 H) 2.55-2.64 (m, 2 H) 1.37 (s, 9 H). MS: (M+H)+=614. MP = 108-110 ° C. Preparation 1-43 as described in Example 41 (Step 1), but substituting (iS,4S)-2,5-diaza-bicyclo[2·2·1]heptane-2-carboxylic acid tert-butyl ester 1-nonylpiperazine to prepare

(lS,4S)-5-(6-Gaspyrid-3-ylmethyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester.

1 preparation (18,48)-2-(6-gas-indole ratio -3-ylmethyl)-5-mercapto-2,5-diazabicyclo[2.2·l]-heptane: lS,4S)-5-(6-Chloro-pyridin-3-ylmethyl)_2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (l.lg'3.4 Mm0l) I57475.doc -233 - 201211039 Dissolved in a mixture of 11.3 ml of citric acid and 22.6 ml of formalin. The reaction was heated at 70 °C for 4 hours and then cooled to room temperature. Water was added and the aqueous layer was extracted with DCM. The aqueous layer was carefully basified with solid potassium carbonate and extracted three times with DCM. The crude product was purified by chromatography using a DCM gradient of 5% to 25% methanol. Ammonium hydroxide (about 2%) has been added to methanol. Obtained 500 mg of a colorless liquid (61.9 ° / 〇). Example 43

Preparation of 6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3-{l-fluorenyl-5-[5-((lS,4S)-5-fluorenyl-2,5-) Diaza,bicyclo[2.2.1]hept-2-ylindenyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzene Base)-2Η-pyridazine-butanone: using the general procedure described in Example 41, using (lS,4S)-2-(6-a-pyridin-3-ylmethyl)-5-methyl-2 ,5-diazabicyclo[2.2.1]-heptane instead of 1-((6-chloro-bipyridin-3-ylindenyl)-4-mercaptopiperazine in step 2 and using THF containing NaOH Instead of potassium carbonate to remove the acetate-based protecting group to prepare 6-tert-butyl-8-1-2-(2-methyl-indenyl 5-[5-((lS,4S)-) 5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylindenyl)-.pyridin-2-ylamino]-6-sideoxy-1,6-di Hydrogen-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one. Obtained 46 157475.doc -234-201211039 mg (98%) as an off-white powder. lfi NMR (300 MHz, DMSO-t/ 6) δ ppm 9.38 (s, 1 H) 8.54 (s, 1 H) 8.52 (d, J=2.3 Hz, 1 H) 8.20 (d, J=1.9 Hz, 1 H) 7.87 (s, 1 H) 7.72 -7.76 (m, 1 H) 7.64 (dd, J=8.5, 2.1 Hz, 1H) 7.43-7.59 (m, 4 H) 4.58 (t, /=6.0 Hz, 1 H) 4.41 (br. s., 2 H) 3.79 (s, 3 H) 3.49-3.61 (m, 2 H) 3.18 (s, 1 H) 3.09 (s, 1 H) 3.49-3.61 (m, 2H) 2.54-2.66 (m, 2 H) 2.24 (s, 3 H) 1.57 (s, 2 H) 1.38 (s, 9 H) 〇MS: (M+H)+=651.ΜΡ=183-186... Preparation 1-44 Use Example 41 (Step 1-2) The general procedure described in the preparation of 6-gas-4-(5-{[(2-methoxy-ethyl)-fluorenyl) by substituting 2-methoxyethylamine for the methyl piperazine of step 1. Aminol.methyl}-pyridin-2-ylamino)-2-methyl-2H-pyridazin-3-one The secondary amine was protected with a BOC group using standard procedures.

Preparation of 6-chloro-4-(5-{[(2-methoxy-ethylmethyl-aminoindolylbipyridin-2-ylamino)_2-methyl-2-indole-pyridin-3- Ketone: (6-(6-Ga-2-methyl-3-sidedoxy-2,3-dihydropyridazin-4-ylamino). Acridine-3-yl)methyl (2_ Tert-butyl methoxyethyl)carbamate (95 mg, 〇22 mm〇1) was dissolved in sputum 5 blood 157475.doc • 235 · 201211039 citric acid and 1.4 ml of formalin. At 70 ° C The reaction was heated for 4 hours. The reaction was cooled to room temperature, water was added and the aqueous layer was extracted with DCM. The aqueous layer was carefully weighed with a solid carbonic acid needle and extracted three times with DCM. 5% to 5% by use. The crude product was purified by chromatography on a DCM gradient of methanol to afford 50 mg (66%) of white powder.

Preparation of 6-t-butyl_8_fluoro_2_{2-hydroxyindolyl_3·[5·(5_{[(2_曱oxy-ethyl)-methyl-amino]-methyl} -pyridin-2-ylamino)-1-indolyl-6-oxooxyl-M-dihydro-pyridazine-3-ylphenyl}_2Η-pyridazine-one: using the general formula described in Example 41 Procedure with 6-gas-4-(5-{[(2-decyloxy-ethyl)-methyl-amino]-methylpyridin-2-ylamino)_2_indolyl-2H- Pyridazine-3-one substitution step 6 _ 6-gas-2-mercapto_4_(5_((4_mercaptopiperazin-i•yl)indolyl).pyridin-2-aminol) build. Preparation of 6-t-butyl-8-fluoro-2-{2-hydroxymethyl_3·[5_(5-{[(2-methoxy-ethyl)) by Qin-3(2H)-ketone胺 ] 甲基 甲基 甲基 比 比 比 比 比 比 卜 卜 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 丨 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣Reaction), using (2-(ethyloxymethyl)_3-(6-t-butyl-8-fluoro_indolyloxypyridazinyl)phenyl) three-decreasing acid clock (1.2 equivalents) Alternative acetic acid 2-(6-t-butyl-8-fluoro-1-yloxy 157475.doc -236- 201211039 blowing. Qin-2(1H)-yl)-6-(4,4,5,5 - Four f-base-to, 〗-dioxos-2-yl) benzoic acid. After the potassium carbonate-containing methanol was removed to remove the acetoxy group, water was added dropwise, and the reaction was stirred overnight at room temperature. The solid formed was filtered, washed sequentially with water, H, and dried in a vacuum to give 52 mg of crystalline white solid. 〖η NMr (3〇〇MHz, dms〇〇δ 1.38 (s, 9 Η) 2.13 (s, 3 Η) 2.47 (s, 2 Η) 3.22 (s, 3 Η) 3.39- 3.49 (m,4 Η) 3.79 (s,3 Η) 4.43 (br. s.,2 Η) 4·58 (br. s·,1 H) 7.41-7.65 (m, 5 H) 7.75 (d, 7=13.22 Hz, 1 H) 7.87 (s, 1 y H) 8.17 (s, 1 H) 8.46-8.59 (m, 2 H) 9.40 (s, 1 H) 〇MS: (M+H)+=628. Preparation 1-45 Example 45

6_(4.Methyl-Nymidine small base)_嚷嘻_3 base amine: Dissolve the chloro-propanol-based small amine (2.0 g' 15.4 〇 uo uo equivalent) in imethyl piperazine (i55 g) , 154 _ 〇 1 '10.0 eq.), and heated in a sand bath for 4 hours under a machine. The reaction mixture was then heated in a microwave reactor at 20 () t for an hour. The crude product was purified by chromatography using d c m containing i 〇 % methanol (containing about 2% chlorohydrin). To the still impure product, sodium hydrogencarbonate was added to dissolve the 157475.doc-237-201211039 solution and DCM, and the layers were separated. The aqueous layer was back extracted twice with DCM. The combined organic layers were dried with EtOAc EtOAc (EtOAc)EtOAc. 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{l-methyl-5-[6-(4_曱基_〇底°秦-1-yl)-°达°秦-3-ylamino]]6_sideoxy-1,6-·-gas-chimazine _3_yi) phenyl)-2H- °大唤-1 -嗣: use example 41 General procedure for the use of (2-(ethinoyloxymethyl)-3-(6-t-butyl-8-fluoro-1 - pendant oxy. tertyl 2(1H)-yl)phenyl) Potassium trifluoroborate (1.2 equivalents) instead of acetic acid 2_(6_t-butyl-8-fluoro-1-o-oxetazine-2(1H)-yl)-6-(4,4,5,5- Preparation of 6-t-butyl-8-fluoro-2_(2_μmethyl-3-{l-methyl-5-[6-) with tetramethyl-13 2 diboron-2-yl) benzyl ester (4-indolyl-η bottom. Qin-1-yl)-indole_3_ylamino]_6_ pendantoxy-1,6-dihydroindole-3-yl}-phenyl)-2Η- Pyrazine-1-silk. After removing the acetic acid S-protecting group with methanolic acid-containing methanol, the product was purified by preparative TLC using DCM containing 2 hexanes to afford 30 mg of the final product. 1H NMR (300 MHz, DMSO-g?6) δ ppm 1.38 (s, 9 H) 2.21 (s, 3 Η) 2.34-2.44 (m, 4 Η) 3.44-3.53 (m, 4 Η) 3.79 (s, 3 Η) 4.41 (br. s., 1 H) 4.50-4.61 (m, 1 H) 7.39 (d, /=9.82

Hz,1 H) 7.44-7.60 (m,3 H) 7.66 (d, "7=9.82 Hz, 1 H) 7.75 (d, /=13.22 Hz, 1 H) 7.87 (s, 1 H) 8.45 (s, 1 H) 8.51 (d, J=2.27 Hz, 1 H) 9.38 (s, 1 H) ° MS: (M+H)+=626 ° Preparation 1-46

Process H I57475.doc •238- 201211039

(lS'4S)-5-methyl·2,5-diazabicyclo[221]hept@_2_carboxylic acid tertidine. (lS,4S)-2,5-diazabicyclo[2 2 ]] Gengyuan_2• Formic acid tert-butyl vinegar (2.5 g' 12·6 〇 〇 uo equivalent) was dissolved in 126 (6) methanol. Add formic acid (23.5 ml of 37% aqueous solution) and acetic acid (217 hoppers were added with sodium triethoxysulfonate hydride (4.01 g' 18·9 axis. i 5 〇 equivalent). The reaction was scrambled overnight at room temperature. The reaction was concentrated on a rotary evaporator. DCM and sodium hydrogen carbonate were added to the residue, and the layers were separated. lS,4S)-2-methyl-2,5-diazabicyclo[221]heptane: (1S,4S)_ 5-methyl-2,5-diazabicyclo[2.2.1]g The alkane 2-carboxylic acid tert-butyl ester (2.5 g, 11.8 mmol) was dissolved in a 50 〇 / 〇 mixture of DCM and TFA. The reaction was stirred at room temperature for 1 hour. Evaporate solvent. Add DCM and aqueous sodium hydroxide To the residue' and separate the layers. The aqueous layer was re-extracted twice with DCM. The combined organic layers were concentrated and the crude product was used without purification. Step 3. 6-((lS,4S)-5-A Benzyl-2,5-diaza-bicyclo[2 21]hept-2-yl)-pyridazine- 157475.doc -239- 201211039 3-Amine: 6-chloropyridazine_3_amine (200 mg ,! 54 mm〇1,丨〇〇 equivalent) and (lS,4S)-2-甲• 2,5-Diazabicyclo[2·2.1]heptane (693 mg, 6.18 mmol ' 4.00 eq.) was combined in a small round bottom flask and heated at 2 Torr for 2 hours. The glassy residue was dissolved in DCM and purified by chromatography using a DCM gradient eluting with 0% to 25% methanol (containing 2.5% of EtOAc) to yield about 1 〇〇mg (3 1.6%) brown viscous a crude oil. Step 4. Acetic acid 2-(6-t-butyl-8-fluoro-1-oxo-1H-pyridazin-2-yl)-6-(1-methyl-5-[ 6-((lS,4S)-5_decyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridazin-3-ylamino]-6-sideoxy- 1,6-Dihydro-pyridazine-3-yl}-benzoin: 6-((lS,4S)-5-mercapto-2,5-diaza-bicyclo[2.2.1]heptane- 2-yl)-pyridazin-3-ylamine (100 mg, 0.487 mmol, 1.00 equivalent), 2-(5-odor·-1-fluorenyl-6-oxo-1,6-dihydro-acetate) Pyridazin-3-yl)-6-(6-t-butyl 8-fluoro-1-oxo-1H-pyridazin-2-yl)-phenylmethyl ester (284 mg, 0.512 mmol, 1.05 eq. ), xantphos (42.3 mg '0.073 mmol, 0.15 oz), ginseng (diphenylmethylene propyl hydrazine) - dioxin (0) (33.5 mg, 0.036 mmol, 0.075 eq.) and carbonic acid Absolute (476 mg, 1.46 mmol, 3_00 equivalent) was added to the microwave bottle order. The bottle was capped and purified. Degassed dioxane (about 5 ml) was added via a syringe and the bottle was again purged and backfilled with nitrogen. The reaction was heated in a sand bath overnight at 100 °C. The diatomaceous earth was passed through the reaction and concentrated. By using 〇% to 25°/. The DCM gradient of sterol was chromatographed to purify the crude product. LCMS and NMR showed major impurities. It was used in the next step without further purification. Example 46 157475.doc -240- 201211039 Step 5. 6-Tertibutyl I gas_2_(2_ via methyl_3 {1_methyl repair "a. 5 fluorenyl, aza double soil [2· 2.1]hept-2-yl)-thiazide _3_ylamino; j_6_ oxo-oxime-dihydro-thiazide _3_yl}• Stupid yangshen ketone: will be impure from previous reactions The mixture was dissolved in methanol, potassium carbonate was added, and the mixture was heated at 40 ° C for 1 hour. Water was added and the mixture was stirred at room temperature overnight. The solid formed was dried and dried. By preparative tlc (inclusive)

The crude product was purified by 10% / methanol in DCM. The disc was dissolved twice to give 5 mg of a pale solid. The purity was about 85 Å. . 1h NMR (3〇〇mhz, DMSO-d6) δ ppm i_4〇(s,9 Η) 1.7〇-ι·79 (m,1 η) 1.83-1.92 (m, 1 H) 2.26 (s, 3 H) 2.42 (d, J=9.〇6 Hz, 1 H) 2.70-2.85 (m,1 H) 3.37-3.55 (m,4 H) 3.79 (s,3 H) 4.33-4.66 (m,3 H) 7.06 (d, J=9.82 Hz, 1 H) 7.44-7.57 (m, 3 H) 7.64 (d, /=9.44 Hz, 1 H) 7.75 (dd, 7=13.41, i 7〇Hz&gt; i H) 7.88 ( d, 7=1.89 Hz, 1 H) 8.42 (s, 1 H) 8.52 (d5 /=2.64 Hz, 1 H) 9.32 (s, 1 H). MS: (M+H)+=638. Preparation 1-47 Example 47

157475.doc •241 - 201211039 Preparation of 6-(6-gas-2-fyl-3-oxo-oxy-2,3-di-argon-axazine-4-ylamino)_Final acid

Under heating, the 6-amine is based on acid methyl ester (2 g, 13.1 mmc > i, 1. 〇〇 直), 4- -6- -2- 曱 曱 哒. Qin-3(2H)-one (2.94 g, 13.1 mmol, 1 eq.) and (9,9-dimercapto-9H-dibenzopyrano-4,5-diyl) bis(diphenylphosphine) (400 mg, 691 μιηοΐ '0.0526 equivalent) was dissolved in DMF (300 ml). Under an argon atmosphere, cesium carbonate (128 g, 39.4 mm ,l, 3 equivalents), Pd2 (dba) 3 (301 mg, 329 μηιοί, 0.025 field amount) were sequentially added. Heat the reaction mixture to } 〇 5 it overnight. The crude reaction mixture was poured into water (400 ml), and the obtained precipitate was filtered and washed with water. The resulting filter cake was dissolved in dioxane. The organic phase was washed with EtOAc (EtOAc m. (m+H)+=294.9 m/e Step 2.

157475.doc •242- 201211039

6-(6-Chloro-2-methyl-3-oxo-2,3-dihydroindole-4-ylamino) to methyl acetate (1.523 g ' 5.17 mmo i 〇〇 equivalent) ) suspended in dioxane (10) ml). Add 1 Μ lithium hydroxide (1 〇 3 guabu 1 〇 3 mm 〇 i, 2 when the amount). The light brown suspension was stirred overnight at room temperature. Further 丨M lithium hydroxide (10.3 ml, 10.3 mmol, 2 eq.) was added and stirred over the weekend. A mixture of ethyl acetate/ammonium chloride solution was added to the reaction mixture. The resulting precipitate was collected by filtration. The precipitate was wet-milled with water (200 ml), filtered, washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Cyclobutane_1_carbonylpyridin-2-ylamino]-6-chloro-2-indenyl_ • 2H_jian. Qinshangone

C1 makes 6-(6_氡2-mercapto-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotine 157475.doc -243· 201211039 acid (100 mg, 3 56 Ηηιοί, 1.00 equivalent) was suspended in di-methane. Ethylene dichloride (67.8 1 ^, 46.8 41, 534 4 〇 1 〇 1, 1.5 eq.) and 1 drop of DMF (10 μM) were added in this order, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated. The acid chloride was used as it is in the next step. The acid vapor was dissolved in dioxane (10 ml). Azetidin (20.3 mg, 24.0 μΐ '356 μηιο 1.00 eq.), Diea (23 〇 mg '311 μΐ, 1.78 mmo b 5 equivalents) were added thereto in sequence, and the reaction was stirred at room temperature. . The reaction mixture was diluted with a dioxic broth, washed with a saturated sodium carbonate solution, washed with brine, dried over sodium sulfate, filtered, and concentrated to give a pale brown solid ( 145 mg), which was wet-dried with DCM/Hex/EtOAc. The desired product (56 mg) was obtained as a yellow solid. (M+H)+=320.0 m/e Step 4. Preparation of 2-(3-{5-[5-(azetidinium·carbonyl)pyridinyl-2-ylaminopyridinyl-6-side Oxy-1,6-dihydro-pyridazine_3_yl b 2_hydroxymethyl_phenyl)_6_t-butyl-8-fluoro-2Η-»too sniffing-i_g with 4-(5 -(azetidine-indole-carbonyl)pyridin-2-ylamino)6_gas_2曱ylindole-3-(2H)-one (56 mg, 175 μηιοί' 1.00 equivalent), (2- (Ethyloxyindenyl)-3-(6-tert-butyl-8-fluoro-indole-oxo-oxazine-2-(1Η)yl)phenyl) sessile succinic acid (83.1 mg, 175 μπι〇1,1 eq.), x ph〇s (13 〇mg ' 27.3 μιηοΐ ' 0.156 eq.) and tripotassium phosphate (818 ί, 385 μηηοΐ, 2.2 eq.) dissolved in 1% aqueous solution of decyl alcohol (1 () In the claw", the reactant was degassed. Finally, bis(diphenylarbenium acetonide)palladium (9〇6 mg, 158 μηιοί '〇.〇9 equivalent) was added and the reaction mixture was stirred at 1 〇 (rc) The reaction mixture was filtered, and the filter cake was washed with methanol. The combined filtrate 157475.doc-244-201211039 and washings were concentrated and extracted with ethyl acetate and water. , washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate. EtOAc was evaporated from ethyl acetate. The crude product was purified to give a yellow solid, which was dissolved in dioxane. A solution of sodium hydroxide (263 μL, 263 μηιοί, 1.5 eq.) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was treated with EtOAc (10 EtOAc) (EtOAc) (EtOAc) The crude product was purified by EtOAc (EtOAc) eluting eluting Alkyl group)-° ratio of 2-aminoamino group]-1-methyl-6-sideoxy-1,6-dihydro-oxazin-3-yl}-2-methyl-phenyl) _6-Tertibutyl-8-fluoro-2Η-π太嗓_ι_嗣(16 mg).(Μ+Η)+=610·1 m/e !H NMR (3 00 MHz, gas δ δ ppm 1.42 (s, 9 Η) 2.3 8 (five %, /=7.70 Hz, 2 Η) 3.79 (br. s, 1 H) 3.91 (s5 3 H) 4.25 (br. s., 2 H) 4.43 (br. s., 4 H) 6.99 (d, / =8.69 Hz, 1 H) 7.44- 7.70 (m, 5 H) 8.00 (dd, /=8.69, 2.27 Hz, 1 H) 8.29 (d, 7-2.64 Hz, 1 H) 8.47 (s, 1 H) 8.60 (d, /=2.27 Hz, 1 H) 8.71 (s, 1 H). Preparation I_48 Example 48 157475.doc •245- 201211039

Op was prepared by a procedure similar to that of Example 47, but substituting thiomorpholine 1,1-dioxide for azetidine in step 3 to give 6-t-butyl-2-(3-(5- [5-(1,1-di-oxy-116-thio-indol-4-yl)-° ratio of 2-ylamino]-1-methyl-6-sideoxy-1 ,6-Dichloro-d. Qin-3-yl}-2- fluorenyl-phenyl)-8--- _ 27/-°T-Hin-1-one. (M+H)+=687.9 m /e ]Η NMR (300 MHz, gas-c〇δ ppm 1.43 (s,9 Η) 3· 12 (br. s·, 4 H) 3.76 (br. s, 1 H) 3.91 (s, 3 H ) 4.13 (br. s., 4 H) 4.44 (s, 2 H) 7.04 (d5 J=8.31 Hz, 1 H) 7.44-7.67 (m, 5 H) 7.78 (dd, J=8.69, 2.27 Hz, 1 H) 8.29 (d, 7=2.64 Hz, 1 H) 8.46 (d, /=2.27 Hz, 1 H) 8.54 (s, 1 H) 8.71 (s, 1 H) Preparation 1-49 Example 49

Prepared by a procedure similar to that of Example 47, but using 2-oxa-6-aza-spiro 157475.doc-246-201211039 [3.3] heptane to replace the azetidin in step 3 to obtain 2 swell oxygen Hetero-6-azaspiro[3.3]heptane-6,yl)„biter·2_ylamino)small methyl·&amp; pendant oxy-1,6-dihydroindol-3-yl) _2_(Hydroxymethyl)phenyl)_6_t-butyl. 8-Fluoro-Terazine-1(211)-one. (M+H)+=652.1 m/e 4 NMR (300 MHz, gas-like - a ^ t ^ , , a) ppm 1.43 (s, 9 H) 3.92 (s, 3 H) 4.29-4.61 (m, 6 H) 4.83 (, „ ux ^ ΛΛ ,, (s, 4 H) 7.00 (d , /=8.69 Hz, 1 H) 7.45-7.68 (m, 5 H) 7.98 (aa r 〇^ . ' ; W, /=8.69, 2.27 Hz, 1 H) 8.29 (d, /=2.64 Hz, 1 H 8.50 (si 〇c〇, , r ^ i H) 8.58 (d, /=2.27 Hz, 1 H) 8.72 (s, 1 H) Preparation 1-50 Example 50

Prepared by a procedure similar to that of Example 1, but substituting 2-methyl-2,6-diaza-spiro[3.3] heptane for the azetidination in step 3 to give 6-t-butyl- 8 Fluor-2-(2-(methyl)_3_(1_methyl_5 (5_(6_曱-yl 2,6-diazaspiro[3.3] ng m carbon)) bite_2_ Amino group) _6 oxo octa &amp; diazepazine · 3 yl) phenyl) pyridazine-1 (2H)-fluorene. (Μ+Η)+=665.1 m/e 157475.doc •247· 201211039 ]H NMR (300 MHz, chloroform-&lt;i) δ: ppm 1.38-1.47 (m, 9 H) 2.38 (s, 3 H) 3.52 (br. s., 4 H) 3.91 (s, 3 H) 4.26 (br. s., 2 H) 4.44 (s, 4 H) 6.96 (d, 7=8.69 Hz, 1 H) 7.41-7.78 ( m, 5 H) 7.95 (dd, /=8.50, 2.08 Hz, 1 H) 8.30 (d, /=2.27 Hz, 1 H) 8.48 (s, 1 H) 8.57 (d, J=1.89 Hz, 1 H) 8.68-8.71 (m, 1 H) Preparation 1-51 Example 51

Prepared by a procedure similar to that of Example 47, but substituting N,N-dimercapto-ethane-1,2-diamine for the azetidine of Step 3 to give 6-(6-(3-(6) - tert-butyl-8-fluoro-1-oxophthalazine-2(1H)-yl)-2-(hydroxyindenyl)phenyl)-2-indolyl-3-sideoxy-2, 3-Dihydropyridazin-4-ylamino)-N-(2-(dimethylamino)ethyl)nicotinate. (M+H)+=641.1 m/e !H NMR (300 MHz, chloroform δ: ppm 1.41 (s, 9 H) 2.35 (s,6 H) 2.62 (br. t, J=1.003 1.00 Hz, 2 H 3.56 (t, J=4.90 Hz, 2 H) 3.84 (m, J=7.20 Hz, 1 H) 3.92 (s, 3 H) 4.44 (br. s., 2 H) 6.98 (d, J=8.69 Hz , 1 H) 7.46-7.71 (m5 5 H) 8.14 (d, 7=9.44 157475.doc -248· 201211039

Hz, 1 Η) 8.29 (s, 1 Η) 8.46 (s, 1 Η) 8.72-8.82 (m, 2 Η) Preparation 1-52 Example 52

Prepared by a procedure similar to that of Example 47, but substituting 2-methylamino-ethanol for the heterocyclic firing in step 3 to give 6-(6-(3-(6-secondbutyl-8-) _ 1-Side oxazine-2(1Η)-yl)-2-(hydroxyindenyl)phenyl)-2-indolyl-3-yloxy-2,3-diaza 嘻-4- Amino group)-Ν-(2-ethyl)-indole-methyl final test oxime &amp; amine. (M+H)+=628.1 m/e 4 NMR (300 MHz, gas-c/) δ: ppm .1.39-1.47 (m, 9 Η) 3.15 (s, 3 H) 3.59-3.90 (m, 4 H) 3.91 (s, 3 H) 4.43 (d, *7=5.67 Hz, 2 H) 6.99 (d, *7=8.31 Hz, 1 H) 7.45-7.69 (m,5 H) 7.81 (dd, J= 8.69, 2.27 Hz, 1 H) 8.29 (d, J=2.6A Hz, 1 H) 8.46 (s,1 H) 8.50 (d, /=2.27 Hz, 1 H) 8.70 (s, ΓΗ) Preparation 1-53 Example 53 157475.doc -249- 201211039

Prepared by a procedure similar to that of Example 47, but replacing azetidine in Step 3 with azetidine-3-carbonitrile to give 1-(6-(3-(3-(6-) -8-fluoro-l-side oxazine-2(lH)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydro Pyridazin-4-ylamino)nicotinoindolyl)azetidin-3-carbonitrile. MS (ml) = 633.2 lU NMR (300 MHz, chloroform δ: ppm 1 · 44 (s, 9 H) 3.54-3.68 (m, 2 H) 3.93 (s, 3 H) 4.44 (s, 2 H) 4.49- 4.71 (m, 2 H) 7.01 (d, "7=8.69 Hz, 1 H) 7.45-7.70 (m, 5 H) 7.98 (dd, "7=1.00 Hz, 1 H) 8.30 (d, 7=2.27 Hz , 1 H) 8.50 (s, 1 H) 8.56 (s, 1 H) 8.73 (s, 1 H) Preparation 1-54 Example 54

201211039 by a procedure similar to that of Example 47, 劁τ衣侑' but with pyrrolidin-3-ol in place of step (iv) of nitrogen (tetra) W(tetra)tributyl_8_fluoro_2_(2•(methyl)_ 3-(5- (5-(3-trans-base t each bite base)% core 2_ylamino) small methyl winter side oxy-1,6-dihydroindol-3-yl) stupid) blowing noise _ ι(2Η)_嗣. (MH)=640.1 m/e iHNMRpOOMHz, gas-like, L-stone δ: ppm i 41 (s,9 η) 1.99 (br. s., 2 H) 3.38-4.00 (m, 9 H) 4 40 /1 ^ n) 4.42 (br. s., 2 H) 4.48-4.60 (m,

1 H) 6.93 7.07 (m,1 H) 7.39-7.72 (m,5 H) 7.80-7.89 (m,1 H) 8.29 (d5 J 2.27 Hz, 1 H) 8.43-8.61 (m, 2 H) 8.70 ( s, 1 H) Preparation 1-55 Example 55

Prepared by a procedure similar to that of Example 47, but replacing the azetidine in Step 3 with a decylamino-pent-3-ol to give 6-t-butyl-8-fluoro-2-(2-(hydroxy) Methyl)-3-(5-(5-(4-hydroxypiperidin-1-carbonyl)pyridin-2-ylamino)-indole_methyl-6-o-oxy-1,6-dihydroanthracene Pyrazin-3-yl)phenyl)pyridazine_ι(2Η)-one. (Μ+Η)+=654·0 m/e. 4 NMR (300 MHz, chloroform 4) δ: ppm 1.42 (s, 9 H) 1.58 (br. s., 3 H) 1.87-2.02 (m, 2 H) 3.29-3.45 157475.doc •251 · 201211039 (m , 2 Η) 3.65 (s, 1 Η) 3.81 (t, 7=1.00 Hz, 1 H) 3.93 (s, 3 H) 3.97-4.07 (m, 2 H) 4.43 (d, /=6.42 Hz, 2 H 6.99 (d, /=8.31 Hz, 1 H) 7.45-7.69 (m, 5 H) 7.76 (dd, /=8.31, 2.27 Hz, 1 H) 8.29 (d, J=2.64 Hz, 1 H) 8.41- 8.45 (ms 2 H) 8.69 (s, 1 H) Preparation 1-56

Pd2(pda)j CsCOj

Xantphos

Example 56 6-Tertibutyl-8-fluoro-2-(2-hydroxymethyl-3-{l-methyl-5-[5-(4-methyl-)-1 -yl)-oxime σ定-2 -ylamino]-6-tertiaryoxy-1,6-diaza-enhanced-3-yl} _phenyl)-2-indole-pyridazin-1-one

157475.doc -252 - 201211039 To a solution of 1-methyl- 4-(6-Shishoyl 0 to 0--3-yl)pyridazine (5 mg, 2.25 mmol) in ethanol (20 mL) I〇% pd/C (80 mg, 0.75 mmol) ' was added and the resulting mixture was stirred under a hydrogen atmosphere for an hour. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. Purging 5-(4-methylpiperazine-1.yl)pyridin-2-amine (172 mg, 〇.9〇mmol), 4-bromo-6-chloro-2-mercaptopyridazine-- with argon 3(2H)-ketone (200 mg, 0.90 mmol), carbonic acid planer (ΐ·〇2 g '3.13 mmol) and 4,5-bis(diphenylphosphino)_ 9,9-monomethyldibenzo a solution of 0 ketone (77.7 mg, 0.13 mmol) in dioxo (1 〇ml) followed by the addition of bis(dibenzylideneacetone)dipalladium (61.5 mg, 0.07 mmol), and The resulting solution was heated at 90 ° C for 18 hours. The mixture was cooled to room temperature and diluted with dichloromethane and water. The layers were separated and the aqueous layer was extracted with chlorobenzene (2.times.25 mL). The organic layers were combined and dried over magnesium sulfate. The resulting mixture was filtered&apos; and concentrated in vacuo. The residue was triturated with decyl alcohol and hydrazine, and filtered and washed with diethyl ether and dried to give 6- gas-4·[5-(4-methyl-piperazine-1-yl) as a yellow solid. Pyridin-2-ylamino]_2-methyl-2-indole-3-one-3-one (223 mg, 74%). Purging 2-(6-t-butyl-8-fluoro-1-oxo-oxazine- 2(1H)-yl)-6-(4,4'5,5-tetramethyl) acetate with argon I,3,2-dioxaboron-2-yl)benzyl ester (221 mg, 〇.45 mm〇l), 6-chloro-4-(5-(4-mercaptopiperazin-1-yl) Pyridine-2-ylamino)-2_mercaptopyridazine_3(2Η)·_(1〇〇,〇3〇面〇1), potassium phosphate (159 mg, 0.75 mm〇i) and two Bath of cyclohexyl (2,4,6,6ι-triisopropylbiphenyl-2-yl)phosphine (14.2 mg, 〇.03 mm〇1) in butanol (4 mi) and water (丨mL) The solution was then added (bis[diphenylmethyleneacetone]dipalladium) (8.59 mg, 157475.doc -253 - 201211039 0.01 mmol) and the resulting solution was heated at 100 ° C for 2 hours. The resulting mixture was cooled&apos; poured into a gasification and a solution and extracted with di-methane (2 mL). The layers were separated and the organic phase was dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was dissolved in dioxane 〇〇 mL) and treated with a lithium hydroxide solution (0.5 mL &apos; 2.0 M), The resulting mixture was poured into a saturated gasification key solution and extracted with dioxane (2 x 50 mL). The layers were separated and the organic phase was dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc EtOAc EtOAc (EtOAc) -T-butyl-2-(3-{5_[5-(4-indolyl-piperazin-1-yl)-pyridine·2, arylamino]-1-indenyl-6-sideoxy- 1,6-Dihydro-indol-3-yl}-2-hydroxyindolyl_phenyl)-8-fluoro-2-indole-inden-1-one (45 11^, 24%): 111卩260- 264. (:; 'Η NMR (300 MHz, DMSO-^6) δ: ppm 1-38 (s5 9 Η) 2.20 (s, 3 Η) 2.33-2.46 (m, 4 Η) 2.98-3.19 (m, 4 Η ) 3.77 (s, 3 Η) 4.27-4.69 (m, 3 Η) 7.24-8.07 (m, 8 Η) 8.32-8.74 (m, 2 Η) 9.23 (s,1 Η) » Preparation 1-57 157475.doc •254· 201211039

Example 57

6-Tertibutyl-2-(3-{5-[5-((S)-l,2-dihydroxy-ethyl)-pyridazin-2-ylamino]-1-methyl-6 -Sideoxy-1,6-dihydro-s--3-yl}-2-methyl-phenyl)-8-fluoro-2pyridin-1-one

(S)-5-(2,2-Dimercapto-1,3-dioxolan-4-yl) was purged with argon. Bisyl-2-amine (prepared as described in Example 54 of WO 2004052869, 175 mg, 0.90 157475.doc -255 - 201211039 mmol), 4-bromo-6-gas-2-hydrazinazine-3(2H)-one ( Mo mg, 〇9〇mmol), cesium carbonate (1.02 g, 3·ΐ3 mmc) i) and 4,5-bis(diphenylphosphino)_ 9,9-didecyldipyridinopyran (77.7 Mg, 0.13 mmol) in dioxane (1 〇 ml): gluten solution, followed by ginseng (diphenylmethylene acetonide) dioxin (〇) (6j 5 mg, 0.07 mmol), and at 90 〇 The resulting solution was heated under c for 18 hours. The mixture was cooled to room temperature and diluted with dioxane (50 mL) and water. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The organic layers were combined and dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The sediment formed by the separation/constraination; the temple, washed with a baker and dried under vacuum to give 6-gas-4-[5-((S)-2,2-di) as a yellow solid Mercaptodioxol-4-yl)-pyrazin-2-ylamino]-2-methyl-2H-pyridazin-3-one (150 mg, 50%). Purging acetic acid 2-(6-t-butyl-8-fluoro-indole-oxetazine-2-(1H)-yl)-6-(4,4,5,5-tetradecyl) by argon Dioxaboron-2-ylphenyl phthalate (3 07 mg, 0.62 mmol), (S)-6-chloro-4-(5-(2,2-dimercapto-i 3_dioxol) Pyridyl-4-yl).pyridin-2-ylamino)-2-mercaptoxazine_3(21&gt;1)-one (15 mg, 0.44 mmol), potassium phosphate (236 mg, 〇.01 mm 〇1) and dicyclohexyl (2,4,6,-triisopropylbiphenyl-2-yl)phosphine (21.2 mg, 〇〇4 claws called butanol (4 ml) and water (1 The solution in mL) was then added (bis[diphenylhydrazinylacetone]dipalladium) (12.8 mg, 0.02 mmol) and the resulting solution was heated at 1 〇〇t: for 2 hours. The resulting mixture was cooled and poured into a gas. In a saturated solution of ammonium chloride, and extracted with dichloromethane (2×100 mL), the layers were separated, and the organic phase was dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) And using a hydrazine hydroxide solution (〇 5 mL, 2 〇 157475.doc -256- 201211039, and the resulting mixture was stirred overnight at room temperature. The resulting mixture was poured into saturated gasification. In an ammonium solution, and extracted with dioxane (2×l 50 mL), the layers were separated, and the organic phase was dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by EtOAc (1⁄4 to 7%). -Dimethyldioxolan-4-yl)pyrazine-2-aminocarbyl)-1-methyl-6-oxirane-1&gt;6-dihydropyridazine_3_yl)_2_( Hydroxymethyl)phenyl)-8-fluoropyrazine-1(2H)-one (99 mg, 36%). To (S)-6-tert-butyl·2·(3·(5_(5_(( 2,2_Dimercapto_13-dioxol-4-yl)pyrazin-2-ylamino)_ι_methyl_6_sideoxy_i,6-dihydropyridazine_ To a solution of 3-yl)-2-(hydroxymethyl)phenyl)-8-fluoropyridazine^ (yield of 99%) in tetrahydrofuran (4 mL) (1 〇n, 4 mL) The resulting mixture was stirred overnight at rt. The mixture was taken from EtOAc EtOAc (EtOAc m. Residue Recrystallization from dichloromethane and isopropyl acetate gave 6-t-butyldihydroxy-ethyl)pyrazin-2-ylamino]-1-methyl_6_ side as an off-white solid Oxydihydro-pyridazine_3_yl-2-hydroxyindole-phenyl)-8-fluoro-2H-pyridazine-1-(i5.4 mg, 170/〇): MP218-224. (: ; 4 NMR (300 MHz, DMSO4) δ ppm 1.37 (s, 10 H) 3.44-3.95 (m, 5 Η) 4.32-4.82 (m, 4 Η) 5.40 (d, J=4.9l Hz, 1 H 7.22-7.99 (m,5 h) 8.16-8.65 (m,3 H) 8.78 (s,1 H) 9.81 (s,1 H). Preparation 1-58 157475.doc •257- 201211039

1) SOCIj MeOH L·An A)

Mcf, DMF N-g 吵介-一-〇-ΝΧν〇Ο,Μ0 Ο,Ν^ρ〇n

Cl

◊H D1FEA THF PBr3 CHCI3 °^YV^Br N-N,

Pd2(pda)3 CsC03 Xantphos 1) Pd2(pda) kh2p〇4

Q example 58

Ethyl 12-[5-(5-azetidin-1-ylmethyl-1_methyl-1&amp;1! ratio. sitting_&gt; base-based)-1-methyl-6-side oxygen Base-i,6-dihydro-pyridazine_3_yl]_6(6_t-butyl 8-fluoro-1-yloxy-1H-pyridazine-2-yl)_benzol

Ώ Add sulfite to the solution of 5-nitro-iH-indole _3_ decanoic acid (1.13 g, 7.19 mm〇l) in anhydrous decyl alcohol (20 ml) at 〇C Chlorine (2 23 g, 157475.doc • 258· 201211039 1.37 m b 18.7 mmol). The resulting solution was heated to reflux for 2 hours. Evaporation of the cooled solution to dryness afforded 5 <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 87 g,1〇9 mm〇1) Add potassium carbonate, 21.9 mmol) and iododecane (2.02 g, 〇89 mL, 14 2 noodles) to a solution of anhydrous dimethylformamide (20 mL) The resulting solution was stirred for 18 hours at room temperature. The mixture was diluted with water (1 χ 15 〇 ,) and extracted with dichloromethane (3×75 mL). The combined organic layers were dried over magnesium sulfate. The residue was purified by flash chromatography eluting eluting elut elut elut elut elut elut Mixture of methyl pyrazole-3-furoate with methyl methyl-5-nitro-1H-pyrazole-3-carboxylate (164 g, 81%) 〇 at 0 C to 2-methyl-5- Nitro-2H-n is compared with sali-3-carboxylate and decyl-5-nitro-1H-pyrazole-3-decanoate (1.18 g, 6.37 mm〇1) in tetrahydrofuran (20 mL) Lithium aluminum hydride solution (丨〇M, in tetrahydrofuran, 7.65) was added dropwise to the solution mL, 7.65 mm 〇l). The resulting mixture was stirred at (TC) for 20 minutes. Ethyl acetate (1 mL) and a little sodium sulfate decahydrate crystals were sequentially added to the solution. The mixture was stirred for 3 hrs, then filtered. The filter cake was washed with ethyl acetate and the filtrate was evaporated. EtOAcjjjjjjjj Methyl _3_nitro_1H_pyrazole _5_ yl)methanol (496 mg, 50 〇 / 〇). At 0C 'via syringe, to (丨_曱-3-3-nitropyrazole _5_ 157475.doc -259- 201211039 base) sterol (496 mg, 3.16 mmol) was added dropwise to a solution of three desertification scales (854 mg, 0.30 mL, 3.16 mmol) in a solution (10 mL). The mixture was warmed to room temperature, and stirred for 1 hour. The resulting solution was cooled to hydrazine. (3, and diluted with a gas mixture (50 ml). The obtained solution was tested with saturated aqueous sodium hydrogencarbonate (2 〇 (pH 8.5). The layers were separated and the aqueous layer was extracted with EtOAc (EtOAc). The residue was purified by EtOAc (EtOAc) elut elut Mercapto-3_nitro heart^pyrazole^% mg, 630/〇). To a solution of 5-(bromoindolyl)-1-indolyl-3-nitro-1H-pyrazole (436 mg, 1.98 mmol) in tetrahydrofuran (10 mL), aq. Mg' 0.17 mL, 2_48 mm 〇l) and 'diisopropylethylamine (3 〇 7 mg, 0.42 mL, 2.38 mmol), and the mixture was stirred at room temperature for one hour. The solution was concentrated, and the residue was crystalljjjjjjjjjj The aqueous layer was extracted with di-methane (2×5 mL) and organics were combined and dried over magnesium sulfate. The mixture was filtered and evaporated, and purified by flash chromatography (40 g, EtOAc (EtOAc) The small methyl 3-nitro-1Η-β sits (β, 349 mg, 90%). Treat the solution with 5/(nitrogen heterocycle methyl INilulu ratio ° sitting (349 y, W job. (10) ethanol (20 mL) with hydrogen/carbon (1 〇%, 50 mg). The resulting mixture was chilled. The reaction mixture was filtered through a Shih-hss pad and the pad was washed with ethanol. I57475.doc -260-201211039 concentrated sputum in vacuo was obtained as a faint &amp;# ς / g A &amp; J King recognizes 5-(azetidinylmethyl)_ 1-methyl-1H-pyrazole-3-amine (292 mg, 99%) in a gas-colored oil. -(azetidinyloxymethyl)+methyl_ih.biw_3 amine (292 mg 1.76 mmol), 4-bromo-6-chloro-2-methylpyridazine_3(2H)_ Ketone (393 mg, 1_76 mmol), carbonic acid planer (2〇〇g, 6.15 nickname and 4,5_bis(diphenylphosphino)_9,9-dimercaptodibenzopyran (152 mg, 〇%) Ment) a solution in dioxane (1 〇 ml) followed by the addition of bis(diphenylarylene)

Acetone) dipalladium (0) (121 mg, 0.13 mm 〇i), and the resulting solution was heated at 9 Torr (&gt;c, 1 M, _. The mixture was cooled to room temperature and burnt with two gas (5 〇) Dilute with water, separate the layers, and extract the aqueous layer with methylene methane (2 </ br> 25 mL). The organic layer was combined and dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The ether was washed with diethyl ether and dried under vacuum to give 4-(5-(azetidin-1-ylindenyl)-1-indolyl-1H-pyrazole-3-ylamino) as a pale yellow solid. _6_Chloro-2_mercaptopyridin-3(2H)-one (272 mg, 50%). Purging acetic acid 2-(6-t-butyl_8_fluoro-oxo-oxazine) with argon 2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborene-2-yl)benzophenone (498 mg, 1.01 mmol), 4 -(5-(azetidinylindolyl-1H-.pyridin-3-ylamino)-6-chloro-2-methylpyridazinone (183 mg '0.5 9 mmol) Potassium phosphate (3 15 mg, 1.48 mmol) and dicyclohexyl (2|,4|,6'-triisopropylbiphenyl-2-yl)phosphine (28.31^, 0.06111111〇1) in butanol (4 Ml) and water in water (1 mL) Add (bis [diphenylhydrazinylacetone] dipalladium) (17.0 mg, 0.03 mmol) ' and heat the resulting solution for 2 hours at rc. Cool the resulting mixture and pour into a gasified saturated solution, 157475. Doc • 261 · 201211039 and extracted with 2 gas (2) mL). Separate the layers and dry the mixture with sulphuric acid. The mixture is passed through and concentrated in vacuo. The residue is dissolved in 2. The smoldering (Η) mL) And using a hydrazine hydroxide solution (〇5, 2 〇理, and the resulting mixture was stirred overnight at room temperature. The resulting mixture was poured into a saturated ammonium carbonate solution and extracted with di-methane (2×l 5 mL) The layers were separated and the organic phase was dried <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjh Residue 'obtained acetic acid 2_[5-(5-cycloheptin-1-ylmercapto-1-methyl-1H-° than wow-3-ylamino)-1-A -6-Sideoxy-1,6-dihydro-indole_3_yl]-6-(6-t-butyl-8-fluoro-1-yloxy-1H-. Too-2 -base)-benzoquinone vinegar (112 mg, 3 2%) : mp 214-217°C ; !H NMR (300 MHz, DMSO-J6) δ ppm 1.01-1.55 (m, 10 H) 1.72-2.08 (m, 2 H) 2.90-3.67 (m, 11 H ) 4.28-4.62 (m, 3 H) 6.08 (s, 1 H) 7.22-8.08 (m, 6 H) 8.50 (d, /=1.89 Hz, 1 H) 9.15 (s, 1 H). Preparation 1-59 157475.doc 262- 201211039 K2COj SOo Acetone LiBH4

Me〇H BrCHjCH^Br JHF Ηζ Br 10% Pd/C MeNH2 EtOIC TTIIF OH Br PBr3 CHCI3

3) PdiipdaJj kh2p〇4 〇2N'^^C〇iIL-^02N*^^C02Me_^Q2N,&gt;t(^y-CO,Me t

Pdi(pda)3 CSC〇3 Xantphos Dioxane X-Phos

Example 59 Acetic acid 2-(6-t-butyl-sideoxyl·1Η. Tert-butyl-2-yl b-6-methyl-5-(5-methyl, 4&gt;5&gt;6,7-tetrahydrogen · 吼 并 [ [ 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15

At 〇 °C, '5-nitro-1H-pyridyl 4 1 m 1:1 azole-3_ formic acid (2 〇g, 12 7 in anhydrous decyl alcohol (20 ml)), moxibustion a Add sulfite gas (3 157475.doc -263- 201211039 2·42 ml '33'1 mmol). Heat the resulting solution to reflux. Maintain for 2 hours to evaporate the cold solution to dryness, and use decyl alcohol (2 〇 ml). The residue was obtained as a residue, and the mixture was dried to give 5 nitro </ br </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Add 3-potassium formate (jg, 5 84 mmol) to a solution of acetone (30 mL) in potassium carbonate (4 〇 4 g, 29 2 claws) and shoulders (3.29 g '1.51 mL, 17.5 mmol), and the resulting solution was heated to reflux for 2 hours. The resulting mixture was cooled to 0. (:, filtered and concentrated, and purified by flash chromatography (yield, 6 g, 2% to 4% acetic acid) The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: 1-(2-Bromoethyl)_3_nitro-1H-pyrazole-5-decanoate (5 〇〇, 1.8 mm The ol) solution in tetrahydrofuran (2 mL) was cooled to EtOAc, and lithium borohydride (78.3 mg, 3.6 mmol) was added portionwise. The mixture was warmed to room temperature overnight. 2 〇ml) and water (5 〇ml). The two-phase mixture was separated and the aqueous layer was extracted with ethyl acetate (3 χ 2 〇 mL). The combined organic layers were dried over magnesium sulfate and filtered and concentrated in vacuo. The residue was purified by flash chromatography (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -(2-&gt;Smelly Ethyl)_3_Nitro_iH-n than 嗤_5_yl)methanol (158 mg, 35%) 〇 (1-(2-&gt; stinyl ethyl)-3- Shi Xiaoji-1Η-° ratio. sit--5-yl) decyl alcohol (482 mg, 1.93 mmol) in a solution of air (20 mL) was cooled to 〇 °c, and tribromide was added dropwise via a syringe. (522 mg, 0.18 mL, 1.93 mmol) 157475.doc -264· 201211039 The resulting solution was allowed to warm to room temperature and stirred for a few hours. The resulting solution was cooled to 〇C and diluted with dichloromethane (50 mi). use And aqueous sodium bicarbonate (2〇 mL) and the resulting solution was made alkaline (PH 8.5). The layers were separated and the aqueous layer was extracted with dioxane (3×20 mL). The combined organic layers were washed with brine (3 mL) and dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo to dryness eluted eluted eluted eluted elution

Addition of amidoxime to a solution of 1·(2-bromoethyl)-5-(bromomethyl)·3_nitro-m-pyrazole (469, 1.5 mmol) in tetrahydrofuran (2 mL) The mixture was stirred for 76 hours at room temperature under tetrahydrofuran + 5 25 mL, 1 Torr. The solution was concentrated, and a mixture of the obtained solid indoleacetic acid (10 mL) and a 10% aqueous solution of aqueous solution (1 mL) was applied to separate layers, and the aqueous phase was extracted with ethyl acetate (2 x 3 〇 mL). The organic layers were combined and dried by sulfuric acid lock. The resulting mixture was filtered and the volume was reduced in the sputum air and the precipitate was removed by filtration. The filtrate was concentrated, and the residue was purified by flash chromatography eluting with EtOAc (EtOAc: EtOAc: EtOAc: 5,6,7-tetrazo-carbazolo[l,5-a]pyrazine (67 mg, 24.%). The 5-methyl-2-nitrotetrahydroquinone ratio was treated with palladium on carbon (10% '20 mg). Sit open [Μ-a]. The specific noise (67 called, 0.37 curry 1) in ethanol (1) rainbow): liquid 'and purged with argon. The resulting mixture was mixed with hydrogen (1 _) and the mixture was partitioned with X-algae, and the mixture was washed with ethanol. The filtrate was concentrated in I to give 5-methyl- ,? · Four winds than saliva [1,5 exoazine-2-amine (72 mg, quantitative). I57475.doc 201211039 Purging 5_methyl_4,5,6,7-four with argon Hydropyrazolo[i,5_a]pyrazine-2-amine (55.7 mg, 0.37 mmol), 4-bromo-6-gas-2-mercaptopyridazine_3(2H)-one (81_8 mg, 0.37 mmol) ), cesium carbonate (417 mg, 1.28 mmol) and 4,5-bis(diphenylphosphino)_9,9-dimercaptodibenzo-β-South (31.8 mg, 0.05 mmol) in dioxane (6) The solution in ml), followed by the addition of bis(diphenylmethyleneacetone) two (0) (25.1 mg, 0.03 mmol), and the resulting solution was heated at 90 ° C for 18 hours. The mixture was cooled to room temperature and used Dichloromethane (5 〇 mL) and water were diluted to separate the layers, and the aqueous layer was extracted with dioxane (2×25 mL). The organic layer was combined and dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. Purification of the residue by flash chromatography (breaking gel, 24 g, 2% to 7% methanol in methane) 6-Chloro-2-indolyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[i,5-a]pyridazine-2-ylamino) as a pale yellow solid Pyridazine, 3(2Η)-one (61 mg, 57%). Purging 2-(6-tert-butyl-8-fluoro-o-oxo- 2 (1H)-yl) acetate with argon -6-(4,4,5,5-tetradecyl-1,3,2-dioxaborin_2•yl) stupid (153 mg, 〇.31 111111〇1), 6-gas- 2-methyl_4_(5_methyl_4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-2-ylamino)pyridazine_3(2H)one ( 61, 0.21 mmol), potassium phosphate (110 mg, 0.52 mm〇1) and dicyclohexyl (2',4|,6,-triisopropylbiphenyl-2-yl)phosphine (9.87 mg, 〇.〇) 2) 1) Solution in butanol (4 ml) and water (1 mL) 'Subsequent addition (bis [diphenylarbenylacetone] dipalladium) (5.95 mg, 0.01 mmol) 'and at 1〇〇 The resulting solution was heated for 2 hours. The resulting mixture was cooled, poured into a saturated aqueous solution of ammonium chloride, and extracted with dioxane (2×1 〇0 mL). The layers were separated and dried over magnesium sulfate. Concentrate in vacuo and dissolve the residue 157475.doc -266- 201211039 in dioxane (10 mL) The mixture was treated with a lithium hydroxide solution (〇$ mL, 2.0 Μ) and the resulting mixture was stirred overnight. The resulting mixture was poured into a saturated ammonium sulfate solution and extracted with dichloromethane (2×l 5 mL). The layers were separated and the organic phase was dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc EtOAc (EtOAc) -1-Sideoxy_ih_pyridazine_2_yl)-6-[1-methyl-5-(5-mercapto-4,5,6,7-tetrahydropyrazolepyrazine-2 -ylamino)-6-o-oxy-# 1,6-dihydro-pyridazin-3-yl]-benzoate (56 111 §, 460 / 〇): 111 188 · 193 ° C; 4 NMR (300 MHz, DMSO-A) δ ppm 1.37 (s, 9 H) 2.34 (s, 3 H) 2.77 (t, J = 5.29 Hz, 2 H) 3.50 (s, 2 H) 3.63-4.06 (m, 5 H) 4.17-4.67 (m, 3 H) 5.98 (s, 1 H) 7.33-8.05 (m, 6 H) 8.50 (d, *7 = 2.64 Hz, 1 H) 9.24 (s, 1 H). Preparation 1-60

157475.doc 267· 201211039 K2C〇3 Acetone BrCH2CH2Br 〇2

SOCl2 McOH C〇zH

C〇2Me

Br

LiBH4 THF 〇2N^^C〇2Me N-N

Br

H2 10% Pd/C Eton

THF

Pd^pda), CsCO, Xantphos Dioxane 1) Pdjipda^ KHjP04

Example 60 2-(6-Tert-butyl-8-fluoro-1-o-oxy-1H-pyridazin-2-yl)-6-[1-methyl-5-(5-oxo-dip) Appearance-3 -yl-4,5, 6, 7 -four wind-atb a sit and [1,5 - α] ° ratio 0 Qin _ 2-aminol group)-6-side oxy-1,6 - Second wind - Daxuan-3-yl] - the purpose of this book

Add ruthenium sulphide to a solution of 5-nitro-1 oxime-benzazole-3-decanoic acid (4.88 g, 31·1 mmol) in anhydrous decyl alcohol (50 ml) at 0 °C. (9.61 g, 157475.doc -268 - 201211039 5.9 ml '80·8 mmol). The resulting solution was heated to reflux for 2 hours. Evaporation of the cooled solution to dryness afforded a 5-Ni. 2H-0 ratio as an off white solid. Sodium-3-carboxylic acid methyl ester (4.58 g, 86%). To the 5-stone base -1H-port ratio. Add potassium carbonate (241 g, 174 and 1,2-di Moyiyuan (19.7 g,) to a solution of _3_carboxylic acid formazan (5 97 g, 34 9 〇1) in acetone (100 mL). 9.02 m Bu 1G5 mmol), and the resulting solution was heated to reflux for 2 h, then stirred overnight at room temperature. The mixture was filtered and concentrated and purified by flash chromatography (EtOAc, s. The residue was purified by EtOAc to EtOAc (EtOAc: EtOAc) 〇/〇) ° Add (^-bromoethyl)_3 nitro group to a suspension of lithium borohydride (755 mg, 34 7 mm〇i) in tetrahydrofuran (100 mL) at 〇 °C _ih_ ratio. sit a solution of 5-methyl formate (4.82 g, 17.3 mmol) in tetrahydrofuran (10 mL) while maintaining the temperature below 〇t. Stir the solution at room temperature 2 Ethyl acetate and water (20 ml) were added slowly to the obtained mixture. The mixture was separated and the aqueous layer was extracted with ethyl acetate (3 χ 2 〇mL). The combined organic layers were dried over magnesium sulfate and filtered. The compound was concentrated in vacuo to give (1-(2-bromoethyl)-3·nitro-1H-pyrazol-5-yl)methanol (4.24 g, 98%). A solution of (1-(2-bromoethyl)_3_nitro-1H-pyrazole-5-yl)methanol (4 24 g, 17·mmol) in chloroform (1 mL) was cooled to EtOAc.匸, and add three desertifications (4.59 g, 1.6 m Bu 17.0 _〇1) via a syringe. Allow the jin to pay; the gluten solution is warmed to the temperature, and the mixture is stirred for 2 hours. The solution is cooled to 157475.doc -269- 201211039 〇C, and diluted with a gas p-alkane (5 〇m). The resulting solution was made basic (pH 85) with saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with EtOAc (3 mL, EtOAc). Purification of the residue from 15% to 4% EtOAc EtOAc EtOAc (EtOAc: (3.56 g, 67%). Dibu(2-bromoethyl)-5-(bromo Add oxetane-3-amine (140 mg, i.92 mm) dropwise to a solution of _3_nitro-1H-pyrazole (5 〇〇 mg, 1.6 mmol) in acetonitrile (20 mL) 〇i) and diisopropylethylamine (372 mg, 〇5〇m b 2.88 mm 〇l), and the resulting mixture was stirred at room temperature for 24 hours. The solution was concentrated, and the residue was crystalljjjjjjjjjjj The resulting mixture was filtered and evaporated to dryness crystals crystals crystals crystals _5_oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo-pyrazine (255 mg, 71%). Treatment of 2-nitro-5-oxetan-3-yl- 4,5,6,7-tetrahydro-pyrazolon,5._a]pyridin with palladium on carbon (10%, 60 mg) A solution of oxazide (255 mg, i13 in EtOAc (20 mL)) eluting with argon. The reaction mixture was filtered through a pad of Celite, and pad was washed with ethanol. Concentrate the filtrate in vacuo to give 5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[i,5-a]pyrazine-2-amine as an off-white solid (2 17 mg, 99%) 吹 Purge 5-oxetane _3·yl _4,5,6,7-tetrahydro-pyrazole with argon [u- 157475.doc -270· 201211039 a] azine-2-ylamine (11 〇mg '0.57 mmol), 4-bromo-6-gas-2-methylazine--3(2H)-one (127 mg, 0.57 mmol), carbonic acid planing ( 646 mg, i 98 mmol) and 4,5·bis(diphenylphosphino)-9,9-dimethyldibenzophenan (49.2 mg, 0.08 mmol) in dioxane (8 ml) The solution was then added with bis(diphenylarbenium acetonide) dipalladium (0) (38.9 mg, 〇.〇4 mm〇i), and the resulting solution was heated at 9 ° C for 18 hours. The mixture was cooled to room temperature and diluted with dichloromethane (50 mL) and water. The layers were separated and the aqueous layer was extracted with dichloromethane (2 EtOAc). The organic layers were combined and dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The precipitate formed was separated by filtration, washed with diethyl ether and dried in vacuo to give 6 gas, m.p. 4,5,6,7-tetrahydro-o ratio η sits and [i,5_a]abiazine-2-ylamino)-2H-pyridazin-3-one (113 mg, 59%) » with argon Gas purged 2-(6-t-butyl-8-fluoro-1-o-oxoxime _ 2(1H)-yl)-6-(4,4,5,5-tetradecyl_1 ,3,2-dioxaboromid-2-yl)benzyl ester (249 mg, 〇.5〇mmol), 6-chloro-2-methyl_4_(5-oxetane_3_yl_4 ,5,6,7-tetrahydro-pyrazolo[ua]pyrazine-2-ylamino)_2H_pyridazine-3-one (113 mg '0.34 mmol), potassium acetate (178 mg '0.84 mmol) And a solution of dicyclohexyl (2,4,6'-triisopropylbiphenyl-2-yl)phosphine (16.0 mg, 0.03 mmol) in butanol (8 mi) and water (2 mL). Subsequent addition of (bis[diphenylideneacetone]dipalladium) (9.65 mg '0_02 mmol) at 1 Torr. The resulting solution was heated under the arm for 2 hours. The resulting mixture was cooled, poured into a vaporized ammonium saturated solution, and extracted with dichloromethane (2×l 〇〇 mL). The layers were separated and the organic phase was dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and EtOAc (EtOAc) The resulting mixture was poured into a saturated ammonium carbonate solution and extracted with a gas purge (2 x i 〇〇 mL). The layers were separated&apos; and the organic phase was dried over magnesium sulfate. The mixture was mixed and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc EtOAc (EtOAc:EtOAc) Fluoro-1-oxooxy-1H-pyridazin-2-yl)-6-[1-indolyl-5-(5-oxetan-3-yl-4,5,6,7-tetra Nitrogen-〇 圭 圭 [1,5 -a]e ratio ° Qin-2-ylamino)-6-sideoxy-1,6-diaza-indol-3-yl]-benzaldehyde vinegar ( 113 mg &gt; 54%) : mp 180-185〇C ; NMR (300 MHz, DMSO-J6) δ ppm 1.37 (s, 9 H) 2.66-2.92 (m, 2 H) 3.40-3.83 (m, 6 H 3.98 (t, J=5.48 Hz, 2 H) 4.26-4.82 (m, 7 H) 6.01 (s, 1 H) 7.36-8.00 (m,6 H) 8.50 (d, *7=2.64 Hz, 1 H ) 9.25 (s, 1 H). Preparation 1-61

Process I

Step 1. Preparation of tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-decanoate 157475.doc -272- 201211039

Tetrabutyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate (3 g ') at 50 psi in the presence of 10% Pd/C (314 mg, 295 μηιοί) 9.83 mmol) of sterol (50 ml) was hydrogenated overnight. The catalyst was filtered off and the filtrate was evaporatedjjjjjjjj (M+H)+=278 m/e. Step 2.

Preparation of 4-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylic acid Tributyl ester

This reaction was carried out under conditions similar to those described in Step 6 of Preparation 1-6.

4-Bromo-6-chloro-2-indolylpyridazin-3(2H)-one (2.42 g, HU mm〇1), 4-(6-aminopyridin-3-yl)piperidin-1- Vacuum degassing of a solution of tert-butyl formate (2.73 mg, 9 83 mmol), Xantphos (853 mg, 1.47 mmol) and carbonic acid (9 61 , § 29.5 mmol) in anhydrous dioxane (80 ml). And placed under an argon atmosphere. To the mixture was added bis(diphenylarbenzinone)dipalladium(0) (203 mg, 197 μηιοί)' and the vacuum degassing cycle was repeated. The material was heated overnight at 90 ° C (oil bath) with vigorous stirring. The flask was cooled to ambient temperature and used in two. The smoldering was thoroughly washed and the transitional contents 'concentrated liquid' was passed through the Shixiazao soil and wet-ground with a 1:1 ratio of diethyl ether/ethyl acetate. This gave the desired product as an off-white powder (2 73 , I57475.doc • 273 · 201211039 71.2%). (M+H)+=420.2 m/e. Step 3. Preparation of 4-(6-(6-(3-(6-tert-butyl-8-fluoro-1-yloxy)azine-2-(ih)yl) 2-(hydroxyindenyl)phenyl -2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

This reaction was carried out under conditions similar to those described in the above Step 7 of Preparation Example 6. 4-(6-(6-Ga-2-indolyl-3-oxo-2-3 _Xinyl 4-ylamino) ruthenium was derivatized with nitrogen. Third butyl ester (15〇mg μπιοί), 2-(6-t-butyl-8-fluoro-oxo-oxazine-2(1h)yl)-6-(4,4,5,5-four Mercapto-1,3,2-dioxazepine. East-2-yl) phenyl decyl ester (177 mg, 357 μιηοΐ), xPhos (17 mg ' 35·7 μηι〇ι) and potassium phosphate (19 〇 mg , 893 μιηοΐ) was degassed in 10 ml of dioxane/water (9:1) for 1 min, and bis(diphenylarbeniumacetone) (0) (10.3, 17.9 μπιοί) was added. The reaction mixture was heated to 100 ° C for 2 hours. After treatment, by using 5 ° /. The product was purified by silica gel preparative HPLC eluting to EtOAc (EtOAc: EtOAc) Step 4. Preparation of 4-(6-(6-(3-(6-tert-butyl-8-fluoro-1-yloxy)-2(1H)-yl)- 157475.doc •274· 201211039 2-(Hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3·dihydropyridazin-4-ylamino) 0 to 0--3 -yl) -1 - formic acid tert-butyl vinegar

This reaction was carried out under conditions similar to those described in Step 8 of Preparation 1-6 above. After treatment, the desired product (85 mg '40.9%) was obtained. (Μ+Η)+= 710.5 m/e. Example 61 Step 5. Preparation of tert-butyl-8-gas-2-(2-(methyl)-3-(1-methyl-6-oxo-5-(5-(piperidin-4) -yl) acridine-2-ylamino)-1,6-dihydropyridazin-3-yl)phenyl)pyridazine-1(2H)-one

4-(6-(6-(3-(6-tert-butyl-8-fluoro_1_) side oxygen was treated by treatment with dioxane (10 mL) containing 50% trifluoro acid for 2 hours. Pyridazine_2(1H)_*)_2_(hydroxymethyl)phenyl)-2-methyl-3-oxooxy-2,3-dihydropyridazine-4-ylamino)pyrridine 3 Base) B bottom determination _1_carboxylic acid second butyl ester (85 I). Remove the protecting group. Concentrate the reaction mixture to dry, then partition between ethyl acetate and saturated 157475.doc -275 - 201211039 sodium bicarbonate The organic phase was dried over sodium sulfate, filtered and concentrated. EtOAc was purified from EtOAc EtOAc. Mg ' 65.7%). (M+H)+=610 m/e. NMR (300 MHz, chloroform-d) δ: 8.63 (s, 1H), 8.27-8.33 (m, 2H), 8.21. (d, J =2.0

Hz, 1H), 7.44-7.72 (m, 6H), 6.94 (d, J=8.5 Hz, 1H), 4.46 (s, 2H), 3.88-3.96 (m, 3H), 3.35-3.44 (m, 2H) , 2.85-2.99 (m, 2H), 2.65-2.78 (m, 1H), 1.83-1.97 (m, 4H), 1.43 (s, 9H). Preparation 1-62 Example 62 Preparation of 6-t-butyl _8_fluoro_2_(2_(hydroxyfyl)_3_(1_methyl_5 (5 (1(fluorenylsulfonyl)-piperidine-4) -yl) acridine-2-ylamino)-6-hydroxyl_1,6-dihydropyridazin-3-yl)phenyl)pyridazine_i(2H)-one

In a 10 mL round bottom flask, 6_t-butyl-8-fluoro-2_(2_(methyl)-3-(1-indolyl-6-sideoxy-5-(5-(piperider) Pyridin-4-yl)"pyridin-2-ylamino)- 1,6-dihydropyridazin-3-yl)phenyl)pyridazine_1 (2-acetone (35.03 11^, 57.5 μιηοΐ, 1.00 eq.) in combination with DCM (3 ml) and cooled to 〇.〇 Add DIPEA (8.91 mg, 12.0 μΐ, 68.9 μηη〇1, 1.2 eq.) followed by methane sulfonium (6.58 mg ' 4.48 μb 57.5 ι η 。 1 。 搅拌 搅拌 搅拌 搅拌 搅拌 搅拌 搅拌 搅拌 搅拌 搅拌 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 157 The crude material was purified by EtOAc EtOAc (EtOAc: EtOAc) 8.48 (br· s., 1H), 8.29 (br. s., 1H), 8.20 (br. s·, 1H), 7.42-7.70 (m, 6H), 7.04 (d, J=8.2 Hz, 1H) , 4.42 (br. s., 2H), 4.11 (q, J=7.〇Hz, 2H), 3.95 (d, J=11.3 Hz, 2H), 2.82 (s, 3H), 2.74-2.81 (m, 2H), 2.62 (t, J=11.5 Hz, 1H), 2.04 (s, 3H), 1.77-1.99 (m, 4H),1·42 (s, 9H). Preparation 1-63 Step 1. Preparation of 4-(5-(1-ethylhydrazinopiperidinyl)pyridine-2-ylamino)-6-ox-2-mercaptopyridazine-3 ( 2H)-ketone

In a 5 〇 mL round bottom flask, 4-(6-nitropyridine-3-yl)-5,6-dihydrogen ratio was used. Ding-1(2H)-carboxylic acid tert-butyl ester (250 mg, 819 μιηοΐ, 1.00 eq.) was combined with DCM (2.5 ml) to give a pale yellow solution. Tfa (5 mL) was added, and the obtained mixture was stirred at room temperature for 1 hour until the reaction was completed as determined by LCMS. The crude reaction mixture was concentrated in vacuo and the residue obtained was taken in DCM and cooled to 0. 〇Add ΤΕΑ(228 μbu 1.64 ′ 2_00 equivalent)' followed by dropwise addition of acetic acid chloride (58, 157475.doc 819 -277-201211039 μπιοί ’ 1 〇〇 equivalent). The reaction was allowed to warm to room temperature. After half an hour, the reaction was treated by extraction into ethyl acetate. The organic layer was washed with EtOAc (EtOAc m. (M+H)+=247.9 m/e. This product was dissolved in decyl alcohol (15 ml) and was hydrogenated overnight at 50 psi in the presence of 10% Pd/C (87.2 mg, 819 μM). The catalyst was filtered off and the filtrate was concentrated in vacuo and was used in the next reaction without further purification. For 4-bromo-6-chloro-2-indolylpyridazin-3(2Η)-one (201 mg, 901, 1-(4-(6-amino group) than bite-3-yl). Bottom bite- I_base) B-(18 ,, μιηοΐ), Xantphos (35.5 mg, 61.4 4111 &lt;^) and cesium carbonate ((10)! mg, 2.46 mmol) in anhydrous dioxane (6 ml) Gas, and placed under argon atmosphere. Add bis(diphenyl V-acetone) dipalladium (0) (8.48 mg ' 8.19 μηιοί) to this mixture, and repeat the vacuum degassing cycle. At 90 ° C (oil The mixture was heated under vigorous stirring overnight. The flask was cooled to ambient temperature, and the contents were filtered through a plug of diatomaceous earth with sufficient rinsing with dioxane. The combined filtrate and washings were concentrated and 1:1. The resulting residue was triturated with EtOAc/EtOAc (EtOAc:EtOAc:EtOAc 2-(3-(5-(5-(1-Ethylpiperidine-4-yl)pyridin-2-ylaminomethyl-6-yloxydihydropyridazine_3_yl)_2_( Hydroxymethyl)phenyl)t-butyl-8-fluoropyridazine-1(2H)-one 157475.doc •278· 201211039

This reaction was carried out under conditions similar to those described in the above Step 7 of Preparation Example 6. 4-(5-(1-Ethyl sulfanyl _4_yl) is made by gas. σ _2 _ _ _ _ _2 _2 _2 _ _ _ _ _ ( ( ( ( ( ( ( ( ( ( ( ( -ketone (66 mg, 182 μηιοί), 2-(6- • tert-butyl-8-fluoro-1-indolylpyridazine-2(1Η)-yl)-6_(4,4,5, 5-tetramethyl- 1,3,2-dioxaborom-2-yl)benzoquinone (90.2 mg, 182 μηιοί), xPhos (8.7 mg, 18.2 μlol) and potassium phosphate (96.8 mg, 456 μmol) The solution in 10 ml of dioxane/water (9:1) was degassed for 10 minutes and bis(diphenylfuranyl)palladium(0) (5.24 mg, 9.12 μηιοί) was added. The reaction mixture was heated to 100 C for 2 hours. After the treatment, the product was purified by silica gel preparative HPLC using a gradient from 0 〇 / 〇 to 5% decyl alcohol / ethyl acetate. This gives a 1:1 ratio of the desired compound to the acetic acid 2_(5_(5_(1-ethylsulfonylpiperidine-4-yl)) ° ° bite 2-amino-based)]-methyl-6-sideoxy -1,6-dihydropyridazine_3_yl)-6·(6·t-butyl-8-fluoro-l-oxyxazine-2(1Η)-yl)benzoquinone. The resulting mixture was dissolved in methanol (4 ml), and 2 N Na〇H (468 μM) was added thereto. The reaction was stirred at ambient temperature for 56 hours. The sterol was removed by evaporation, and the resulting solution was acidified with 1 N HCl and extracted with Et EtOAc. The organic extract was washed with water, dried <RTI ID=0.0> The crude residue was purified by EtOAc (EtOAc) eluting Mg , 157475.doc -279· 201211039 26.2%). (M+H)+=652.5, 653.7 m/e. 4 NMR (300 MHz, gas-d-d) δ: 8.57 (s, 1H), 8.41 (br. s., 1H), 8.28 (br. s·, 1H), 8.19 (br. s., 1H), 7.40-7.71 (m, 6H), 6.99 (d, J=8.2 Hz, 1H), 4.80 (d, J = 12.9 Hz, 1H), 4.41 (br. s·, 2H), 4.11 (q, J=7.0 Hz, 2H), 3.85-3.99 (m, 3H), 3.18 (t, J=12.7 Hz, 1H), 2.52-2.83 (m, 2H), 2.13 (s, 3H), 1.89 (t, J=12.7 Hz , 2H), 1.60 (br. s., 2H), 1.38-1.46 (m, 9H). Preparation 1-64 Step 1. Preparation of 4-mercapto-1-(6-stone-chondyl D to 0-but-3-yl). D--4-ol

It will contain a 4-mercapto-branched 4-alcohol (2.72 g, 23.6 mmol), 5-,; odor-2-stone base ratio. Heat (3.2 g ' 15.8 mmol) and tetrabutylammonium iodide (72 mg, 1% μηιοί) in DMSO (2 〇 ml) to 12 〇. (:, maintained for 18 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with water (3 χ 2 〇 mL), then the organic phase was concentrated and dried with diethyl ether to give a yellow solid.

68.2%) 〇 (M+H)+=327.9 m/e 〇 Step 2.

Methylpyridazine-3(2H)-one 157475.doc -280- 201211039

Cl HNxi

N〇 OH

4-methyl-1-(6-nitropyridin-3-yl)piperidin-4-ol (807 mg, at 50 psi in the presence of 10% Pd/C (117 mg, 110 μηιοί) 3.67 mmol) of the solution in methanol (15 ml) was hydrogenated overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo to give 1-(6-aminopyridin-3-yl)-4-merylpiperidin-4-ol. The product was used in the next reaction without further purification. 4-Bromo-6-gas-2-methylindole 0 Qin-3(2H)- _ (902 mg, 4.04 mmol), 1-(6-aminopyridin-3-yl)-4-methylper Pyridin-4-ol (761 mg, 3.67 111111〇1), &amp;1^卩11〇3 (159 111§, 275 4111〇1) and carbonate planer (3.59 g '11 mmol) in anhydrous dioxane ( The solution in 1 〇 ml) was vacuum degassed and placed under an argon atmosphere. To the mixture were added two (0) (38 mg, 36·7 μmol) of ginsyl (diphenylarylene sulfonate), and the vacuum degassing cycle was repeated. The material was heated overnight at 90 ° C (oil bath) with vigorous stirring. The flask was cooled to ambient temperature and the contents were filtered through celite with sufficient rinsing with dioxane and concentrated. The product was purified by silica gel preparative HPLC using a gradient of 5% to 70% ethyl acetate / hexanes. This gave the desired product (807 mg, 62.9%) as a pale yellow solid. (M+H)+=350,352 m/e. Example 64 Step 3. Preparation of 6-t-butyl-8-fluoro-2-(3-(5-(5-(4-hydroxy-4-mercaptopiperidin-1-yl) I57475.doc-281- 201211039 0. Dino-2-ylamino)-1 -mercapto-6-o-oxy-1,6-dihydro-glycan-3-yl)-2-(hydroxyf-yl)-phenyl)indole Pyrazine-1(2H)-one

This reaction was carried out under conditions similar to those described in the above Step 7 of Preparation Example 6. 6-Gatro-4-(5-(4-hydroxy-4-mercaptopiperidin-1-yl)pyridin-2-ylamino)-2-mercaptopyridin-3(2H)-one with nitrogen (150 mg, 429 μηιοί), 2-(6-t-butyl-8-fluoro-1-oxo-oxetazine-2(lH)-yl)-6-(4,4,5,5- Tetramethyl-l,3,2-dioxaboromid-2-yl)benzyl ester (212 mg, 429 μηιοί), xPhos (20.4 mg, 42.9 μηιοί) and potassium phosphate (228 mg, 1.07 mmol) at 10 The solution in ml of dioxane/water (9:1) was degassed for 1 min, and bis(diphenylarbeniumacetone)palladium(0) (12.3 mg, 21.4 μιηοΐ) was added. The reaction mixture was heated to 100 ° C for 2 hours. After processing, by using 〇〇/. The product was purified by silica gel preparative HPLC to a gradient of 5% decyl alcohol / ethyl acetate. This gives a desired ratio of 1:1 ratio to acetic acid 2_(6_t-butyl-8-fluoro-indole-sideoxythiazin-2(1 H)-yl)-6-(5-(5-( 4-hydroxy-4-mercaptopiperidin-1-yl).pyridin-2-ylamino)-1-methyl-6-oxirane-1,6-dihydropyridazin-3-yl) Benzyl methyl ester. The reaction mixture was dissolved in methanol (4 mi), and 2 n NaOH (600 μM) was added thereto. The reaction was stirred at room temperature for 2 hours. The sterol was removed by evaporation, and the resulting solution was acidified with 1 N HCl and extracted with DCM. The resulting organic extract was dried with Na.sub.4, filtered and concentrated in vacuo. The resulting solid was obtained as a yellow solid (yield: 40 mg &apos; 45.8%). (m+H)+=640.4 m/e. NMR (400 MHz, DMSO-c/6) δ ppm 1.14-1.24 (mj 3 H) 1.31-1.48 (m, 12 H) 1-64 (br. s.3 2 H) 2.35-2.68 (ms 2 H) 3.31 (br. ss 2 H) 3.52-3.62 (m, 1 H) 4.41 (d, /=11.29 Hz, 2 H) 7.33-7.60 (m, 7 H) 7.75 (d, /=13.30 Hz, 1 H) 7.87 (s, 1 H) 8.44 (br. s., 1 H) 8.52 (br. s., 1 H). Preparation 1-65 Example 65

Prepared by a procedure similar to that of Example 64, but substituting piperidin-4-ol for the 4-methylpiperidine collar in the step to give 6th butyl winter • fluoro 2 _ (2_ Methyl group-based "pyridyl-2-ylamino"-1.methyl-6-sideoxy],6-dihydro-glycolyl)phenyl)--(2η)- ketone (65 mg ' 38.7%). (m+H)+=626.4 m/e. 屯NMR (400 MHz, gas-like ' δ ppm h41 (s, 9 H) i 64i 77 (m, 2 h) i grab 2.07 (m, 2 H) 2.91 (t, J=9.77 Hz, 2 H) 3.39-3.53 (m, 2 H) 3.80-3.91 (m,3 H) 3.97-4.04 (m,! H) 4 4〇(d , J=6 64 Hz, 2 H) 6.89 (d, /-8.98 Hz, 1 H) 7.28 (br. s., 1 H) 7.42-7.59 (m, 3 H) 7.62-7.67 (m, 1H) 8.03 (br. s.3 1 H) 8.17 (s, 1 H) 8.27 157475.doc -283- 201211039 (d, J=2.34 Hz, 1 Η) 8.45 (s,1 Η) 〇Preparation 1-66 Step 1. Preparation of (1R,5S)-3-methyl-8-(6-nitropyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane

(111,58)-3-Methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (981 mg 5 4.93 mmol), 5- gas-2-nitro. A solution of the bite (100 mg, 4.93 mmol) and triethylamine (4.99 g, 49.3 mmol) in DMS0 (8 ml) was heated to 80 ° C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and brine was washed with saturated sodium sulfate and water. The organic phase was concentrated and dried with EtOAc (EtOAc) Step 2· Preparation of 6-Gas-2-mercapto-4-(5-((lR,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)pyridine -2-ylamino)pyridazine-3(2H)-one

HN 157475.doc •284- 201211039 Preparation of 6-chloro-4-(5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-ylamino)-2- This reaction is carried out under the conditions described in the methyl-pyridazine-3(2H)-one. Containing (lR,5S)-3·methyl-8-(6-nitropyridin-3-yl)-3 at 50 psi in the presence of 10% Pd/C (42.9 mg, 40.3 μηιοί) 8-Diazabicyclo[3.2.1]octane (500 mg, 2.01 mmol) in methanol (15 ml) was hydrogenated overnight. The catalyst was filtered off, and the obtained filtrate was concentrated in vacuo to give 5-(3-mercapto-3,8-diazabicyclo[3.2_1]oct-8-yl)pyridin-2-amine. The product was used in the next reaction without further purification. For 4-bromo-6-gas-2-methylpyridazin-3(2H)-one (492 mg, 2.20 1!1111〇1), 5-(3-methyl-3,8-diazabicyclo[ 3.2.1] Xin-8-yl) &lt;1 to 唆_2-amine (437 mg, 2.0 mmol), Xantphos (86.8 mg, 150 μιηοΐ) and cesium carbonate (1.95 g, 6.00 mmol) in anhydrous dioxane The solution of (1 〇 ml)* was vacuum degassed and placed under an argon atmosphere. To the mixture was added bis(diphenylaryleneacetone)dipalladium(0) (31^' 30 μιηοΐ), and the vacuum degassing cycle was repeated. The reactor was heated under vigorous stirring at 9 (TC (oil bath). The flask was cooled to ambient temperature and the contents were filtered through a plug of diatomaceous earth with sufficient rinsing. The combined filtrate was concentrated. The resulting mixture was triturated with EtOAc (EtOAc) (EtOAcjjjjjjjjjjj Preparation of 6-t-butyl _8_fluoro-2_(2-hydroxyindole_3_p_indolyl_5_[5_((lR,5S)-3-methyl-3,8-diaza-bicyclo[ 3 2"] octyl-8))pyridin-2-ylamino]-6-sideoxy_ι,6-dihydro-pyridazinylphenyl)_211_pyridazinone 157475.doc 201211039

This reaction was carried out under conditions similar to those described in the above Step 7 of Preparation Example 6. 6-Gas-2-methyl-4-(5-((lR,5S)-3-methyl-3 8 -diazabicyclo[3.2.1]-oct-8-yl)σ ratio with nitrogen咬-2-ylamino) 哒; _3 (2h) ketone (150 mg, 416 μπιοί), 2-(6-t-butylfluoro-oxo-oxazine-2(1Η)-yl) -6-(4,4,5,5-tetradecyl-1,3,2-dioxaboron-2-yl)benzyl ester (206 mg ' 416 μιηοΐ), xPhos (19.8 mg, 41·6) Ιιη〇ΐ) and potassium hydride (221 mg, 1.04 mmol) in 1 〇ml dioxan/water (9:1) solution degassed for 10 minutes' and added bis(diphenylarbenium acetonide) palladium ( 〇) 〇 2.0 mg, 20.8 μηιοί). The reaction mixture was heated to 10 ° C for 2 hours. After the treatment, the product was purified by silica gel preparative HPLC using a gradient of 10% to 20% methanol/dichloromethane to afford acetic acid as a pale yellow solid. 1-Sideoxypyrazine-2(111)-yl)-6-(1-methyl-5-(5-(3-indolyl-3,8-diazabicyclo[3.2.1]xin- 8-yl)pyridin-2-ylamino)-6-o-oxy-1,6-dihydropyridazin-3-yl)benzenef ester (69 mg, 24%). (M+H)+= 693, 694 m/e ° 2-(6-Tert-butyl-8-fluoro_1-side oxazine- 2(1Η)-yl)-6-(1) -mercapto-5-(5-(3-mercapto-3,8-diazabicyclo[3.2.1]oct-8-yl)pyridin-2-ylamino)-6-oxirane-1 6-Dihydro-(indol-3-yl)benzaldehyde vinegar (55 mg, 79 μιηοΐ) was dissolved in MeOH (3 ml), and 2 N NaOH (794 157475.doc -286 - 201211039 μΐ) was added thereto. The reaction was stirred at room temperature for 8 hours. The crude reaction was extracted with DCM. The resulting organic extract was dried <RTI ID=0.0>(M </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (M+H)+=651.5, 652.6 m/e » A NMR (400 MHz, chloroform 4) 5 卩? 1111.41(8,9 11)1.59(£1,&gt;/=11.72 1^,111)1.93-2.07 (m, 2 Η) 2.16-2.35 (m, 2 Η) 3.88 (s, 3H) 3.95-4.04 ( m, 1 H) 4.09-4.20 (m, 2 H) 4.40 (d, J=7.03 Hz, 2 H) 5.17-5.40 (m, 3 H) 6.90 (d, 7=8.98 Hz, 1 H) 7.12 (dd , 7=8.98, 2.73 Hz, 2 H) 7.41-7.59 (m, 10 H) 7.65 (d, 7=7.81 Hz, 2 H) 7.91 (d, J=2.73 Hz, 2 H) 8.12 (s, 2 H 8.25-8.31 (m, 2 H) 8.40 (s, 2 H) 〇 Preparation 1-67 Step 1. Preparation of 6-chloro-'(^', /^/,-hexahydro-(3) is bipyridyldonglide Base)·^-mercapto-2H-pyridazin-3-one

4-(6-(6-Ga-2-indolyl-3-oxo-2,3-dihydropyridazin-4-ylamino) prepared as described in Example 29, Steps 1-3 Pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (1.8 g, 4.3 mmol) was dissolved in 15 mL DCM and treated with 7.5 mL of TFA. The reaction mixture was stirred at room temperature for 1 hour. In a vacuum 157475.doc •287- 201211039 Concentrate the crude reaction mixture. The residue was diluted with DCM and sat. NaHC. The extract was dried over Na.sub.2(.sub.4) and concentrated in vacuo to afford s. Step 2. Preparation of 6·Ga-2-methyl_4_(1,_Methyl-Guang^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ketone

In a 25 round bottom flask, 6-chloro-2-indolyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino) phosphine _3(2H), (620 mg , 1 94 _〇1, i 〇〇 equivalent) and A Yue (1.57 g, 1.44 m Bu 19.4 mmo Bu 1 〇 equivalent reading Ding Cai Group ° Get / inflammatory color solution. Add acetic acid (116 mg, 111 μΐ, 1 94 mmo1, 丨.00 eq.). The reaction mixture was cooled to EtOAc. EtOAc (EtOAc, EtOAc, EtOAc. The reaction was completed. The reaction mixture was poured into water. EtOAc EtOAc (EtOAc m. The solid obtained was triturated with diethyl ether to give the desired product (yield: 58 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 4-(1'-indenyl-1|,2',3,,4,5,6,6-hydrogen-[3,4,]bipyridine, 6-ylamino)-2H- Pyridazin-3-one, which was used as such in the next reaction. 157475.d Oc 201211039 Example 67 Step 3. Preparation of 6-t-butyl-8-disorder-2-{2-pyridyl-3-[l-methyl-5-(l'-methyl-1, 2', 3',4',5',6'-hexahydro-[3,4']. Bipyridin-6-ylamino)-6-o-oxy-1,6-dihydro-azine-3 -yl]-phenyl}-2H-呔°Hhen-1-one

6-Chloro-2-methyl-4-(5-(1-methyl-(1)-4-yl)-pyrazine-pyridazine-3(2Η)- Ketone (1.06 g, 3.18 mmol), (2-(ethyloxyindenyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazine-2(1H)-yl) a mixture of potassium phenyl)trifluoroborate (1.51 g, 3.18 mmol), xPhos (227 mg, 476 μηιοί) and potassium phosphate (1·48 g' 6.99 mmol) in 60 ml butanol/water (5:1) Degas ίο min' and add bis(dibenzylideneacetone)palladium (〇) (137 mg ' 23 8 μιηοΐ). The reaction mixture was heated to u〇〇c for 3 hours. The crude reaction mixture was extracted with DCM, washed with water, dried over Na 2 EtOAc, filtered and evaporated The solid was wet-ground with diethyl ether to give a crude product. It was combined with 300 mg of the crude material from the previous batch and purified by silica gel chromatography to give 2-(6-t-butylfluoro-l-oxy-oxazine-2 as a white solid. (1Η).-yl)-6-(1-indolyl·5_(5·(1-methylpiperidin-4-yl)pyridine-2-ylamino)_6_sideoxy_丨,6_ Dihydropyridazine _ 3-yl) This is the purpose of (1,6 g). 157475.doc 201211039 2-(6-Tert-butyl-8-fluoro-1-oxo-oxetazine-2(1H)-yl)-6-(1-indolyl-5-(5-() 1-mercaptopiperidine·4-pyridin-2-ylamino)-6-sideoxy-1,6-dihydropyridazin-3-yl)benzyl ester (1.6 g) was dissolved in 2 mL In the THF, 12 mL of 2 N NaOH was added to the reaction solution, and the reaction mixture was stirred at room temperature. The reaction was not completed. 1 〇 equivalent of 2 n NaOH was further added, and the reaction mixture was further stirred at room temperature for 2 hours. Thf until the reaction mixture is homogeneous, and the reaction is heated to 40 C for 3 Torr. The reaction is cooled to room temperature and stirred overnight. As indicated by LC/MS, the reaction has tended to be complete. To remove most of the THF. The solid formed was collected by filtration. The solid was redissolved in Dcm, filtered over celite pad, washed with water, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The desired product (1.27 g) as a solid. (m+H)+ = 624 m/e. NMR (400 MHz, chloroform (5) δ ppm i 45 (s, 9 h) 1-80-1.92 (m, 5 Η 2.31-2.58 (m, 3 H) 3.03 (d, J=8.28 Hz, 1 H) 3.92 (single peak and overlapping multiplet, 4 H) 4 45 (d, J=6 53 Hz, 2 H) 6.93 (d, 7=8.28 Hz, 1 H) 7.45-7.63 (m, 5 H) 7.65-7.71 ( m, 1 H) 8.22-8.32 (m,3 H) 8.61 (s,1 H) 〇Preparation 1-68 I57475.doc 290- 201211039 ,Br

+ Ν-Ν CI 1) Pd, (pda) 2

Example 68 Preparation of 6-t-butyl-2-(3-{5-[1-((1〇-2,3-dihydroxy-propyl)-11^-oxime. Sodium-3-ylamino) -1-mercapto-6-sideoxy-1,6-di-s-da.qin-3-yl}-2 - fluorenyl-phenyl)-8-^-2Η-Blowing 嗓-1 -商with

吹 Purge (R)-l-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1Η-pyrazol-3-amine with argon ( '177 mg, 0.90 mmol, as prepared in Example 49 of WO2009127546 (A1), 4-bromo-6- ox-2-indole. Benzazine-3(2H)-one 157475.doc -291 - 201211039 (200 mg, 0.90 mmol), carbonic acid planer (1.02 g, 3.13 mmol) and 4,5-bis (one base squaring)_9, a solution of 9-dimercaptodibenzo- 0 bottom (77.7 mg, 0.134 mmol) in dioxane (1 mL), followed by the addition of ginseng (diphenylarbenium acetonide) gemini (0) (61.5 Mg, 0.07 mmol), and the resulting solution was heated at 90 ° C for 18 hours. The mixture was cooled to room temperature and diluted with dioxane and water. The layers were separated&apos; and the aqueous layer was extracted with dichloromethane. The organic layers were combined and dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. Purification of the residue by flash chromatography (j. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Methyl],3_dioxol-4-yl)methyl)-indole-pyrazol-3-ylamino)-2-methylpyridazine-3(2Η)-one (249 mg, 82 %). Purging 2-(6-t-butyl-8-fluoro-1-oxooxazin-2-(1H)-yl)-6-(4,4,5,5-tetramethyl) acetate with argon _1,3,2_dioxaborom-2-yl)benzoquinone (247 mg, 〇.5〇mm〇i), 6_gas_2•methyl_4_(5_oxetane_ 3_yl-4,5,6,7-tetrahydro-indolozolidine.pyrazine_2-ylamino)_2H_pyridazine-3-one (100 mg '0.29 mmol), potassium phosphate (156 mg '0.74 Methyl) and dicyclohexyl (2,4,6,-triisopropylbiphenyl-2-yl)phosphine (14.0 mg, 0.03 mm 〇I) in butanol (4 ml) and water (1 mL) The solution was then added (bis [diphenylidene-S-same] sigma) (8.46 mg, 0.01 mmol) 'and at 1 〇〇. Underarm. Heat the resulting solution for 2 hours. The resulting mixture was cooled, poured into aq. EtOAc EtOAc EtOAc EtOAc (EtOAc) Dissolved in dioxane (1 mL) and treated with lithium hydroxide solution (i 2 · hydrazine) and stirred at room temperature overnight. The resulting mixture was poured over 157475.doc -292· 201211039 In a saturated solution of ammonium sulphate, and extracted with two gas (2 χ丨 5 〇 mL), the layers were separated, and the organic phase was dried over magnesium sulfate. The mixture was concentrated and concentrated in vacuo. , 4〇g, 2% to 丨〇0/sterol of dichloromethane) purification residue 'to give acetic acid 2-(6·t-butyl-8-fluoro-1_) as a pale yellow solid Side oxy-ih_pyridazine·•methyl_ 5-(5-oxetan-3-yl-4,5,6,7-tetrahydro-_«» sits β and [i,5_a] D-pyridyl-2-ylamino)-6-o-oxy-1,6-dihydro-pyridazine_3_ phenyl bromide (138 mg, 72%) « To (R)-6-third Butyl-2_(3_(5_(1_((2,2-dimethyl oxacyclopentan-4-yl)indolyl)-1Η- Zin-3-ylamino fluorenyl _6_sideoxy 丨,6-dihydropyridazin-3-yl)-2-(hydroxyindenyl)phenyl)·8_fluoropyridazine_1(2H) A solution of ketone (135 mg, 0.21 mmol) in tetrahydrofuran (4 mi) was added hydrochloric acid (1·0 N, 4 ml) and the solution was stirred overnight at room temperature. The mixture was extracted with aqueous methane (2 χ 5 〇 mL), and the organic layer was combined and dried over sulphuric acid. The mixture was mixed and evaporated, and the residue was crystallised from methylene chloride and isopropyl acetate. The crystals were washed with diethyl ether and dried to give 6-t-butyl winter (3 { [((R) 2,3, propyl, propyl, s, Oxyloxy-1,6·dihydro-pyridazin-3-yl b 2-hydroxymethyl-phenyl)_8_fluoro_ 2H-Blowing cockroach (52 mg, 41%): 245 25 generations; 1h nmr (over MHZ, face 〇〇S Ppm i.38 (s' 9 Η) 3.67-4.24 (m, 6 Η) 4.27-5.06 (m,5 H)6.l9(d, piece 27Hz iH)7 i8 7 96 (m 7 H) 8.51 (d, /= 2.27 Hz, 1H) 9.23 (s, 1 H) 〇 Preparation 1-69 157475.doc 201211039

Pdz(pda)3 CsCOj Xantphos l)Pd2(pda)2 kh2po4

Example 69 Preparation of 6-t-butyl-2-(3-{5-[5-(4-ethyl-nital.hom-1-yl)-° ratio α定-2-amino group]-1- Methyl-6-o-oxy-1,6-diaza-ruthen. Qin-3-yl}-2-methyl-phenyl)-8-fluoro-2-indole-pyridazin-1-one

Add 10% Pd/C (113) to a solution of 1-ethyl-4-(6-nitro-D-But-3-yl)0 bottom oxime (500 mg, 2.12 mmol) in ethanol (20 mL) Mg, 0.11 mmol), and the resulting mixture was stirred under a hydrogen atmosphere for 18 hr. The algae 157475.doc -294- 201211039 soil filtration reaction mixture was washed with ethanol and concentrated to give N-[(E)-2-(4-ethyl-pyrazine-1-yl) as a gray solid. Penta-2,4-diene-(Z)-subunit]-methylamine (377 mg, 86%). Purging 5-(4-ethyl-bazin-1-yl)pyridine-2-amine (185 mg, 0.90 mmol), 4-bromo-6-chloro-2-methylpyridazine-3 (2H) with argon )-ketone (200 mg, 0.90 mmol), carbonic acid planer (102 g '3.13 mmol) and 4,5-bis(diphenylphosphino)- 9,9-dimercaptodibenzopyran (77 7 mg , 〇13 mmol) in dioxane (1 〇 ml), followed by the addition of bis(dibenzylideneacetone)dipalladium (〇) (615 mg, 0.07 mm〇l) at 9 °C The resulting solution was heated under 18 hours. The mixture was cooled to room temperature and diluted with dichloromethane and water. The layers were separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The organic layers were combined and dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The residue was triturated with decyl alcohol and hydrazine, and filtered and washed with EtOAc and dried to give 6-chloro-4-[5-(4-ethyl-piperazine-l-yl) as a yellow solid. )_pyridine-2-amino-based]_2-mercapto-2Η-βdarind-3-one (138 mg, 44%). Purging acetic acid 2-(6-t-butyl-8-fluoro-indole-oxetazine-2-(1H)-yl)-6-(4,4,5,5-tetradecyl) by argon - Diboron-flavored 2-1-ylphenyl ester (241 mg '0.49 mmol), 6-chloro-4-(5-(4-ethylpiperazin-1-yl)indole-2-ylamino -2-methylpyridazine_3(2H)-one (1〇〇mg, 0.29 mmol), potassium phosphate (152 mg' 〇·72 mm〇1) and dicyclohexyl (2,4,6) a solution of _triisopropylbiphenyl-2-yl)phosphine (13.7 mg, 0.03 mmol) in butanol (4 mi) and water (1 mL), followed by addition (bis[diphenylmethaneacetone] Dipalladium) (8 24 mg, 0.01 mmol) 'and the resulting solution was heated at 100 ° C for 2 hours. The obtained mixed slag was cooled, poured into a saturated solution of ammonium sulfate, and extracted with dichloromethane (2×丨 157475.doc • 295·201211039). The layers were separated and the organic phase was dried over sulfuric acid. Over; do not mix and shrink in a vacuum. The residue was dissolved in two chews (1 Torr) and treated with a hydrazine hydroxide solution (0.5 mL, 2. 〇 Μ), and the mixture was applied overnight at room temperature. The mixture was poured into a saturated ammonium chloride solution and extracted with dichlorohydrazine (2 x 5 mL). The layers were separated and the organic phase was dried with sulfuric acid. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc, EtOAc (EtOAc:EtOAc) Solid 6-tert-butyl-2_(M5_[5♦ethyl_π底?_基基)_〇 _ 2_ylamino]-1·decyl·6_sideoxy-1 ,6-Dihydro-pyridazine_3_ylhydroxyindole-phenyl)-8-fluoro-2H-pyridazine-1-(47mg, 26%): mp 245-247 C - NMR (300 MHz, DMSO-^6) δ ppm 1.02 (t, ^=7.18 Hz, 4 H) 1.38 (s, 10 H) 2.13-2.42 (m, 2 H) 3.09 (br. s·, 5 H) 3.77 (s, 3 H) 4.16-4.72 (m, 3 H) 7.20-8.10 (m, 9 H) 8.28-8.64 (m, 2 H) 9.23 (s, 1 H). Preparation 1-70 Example 7 制备 Preparation of 6-t-butyl-8-fluoro-2·(2_methyl-methyl-based 2-indole-propyl)-1Η-.唾Sial-3-ylamino]-1-indolyl-6-o-oxy-i,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one 157475. Doc -296- 201211039

Purging 1-(3-Amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol with argon (as prepared in Example 7, US 7,935,699 B2, 139 mg, 〇9〇mm 〇1),

4-bromo-6-chloro-2-indolylpyridazin-3(2H)-one (200 mg, 0.90 mmol), cesium carbonate (1,02 g, 3.13 mmol) and 4,5-bis(diphenyl) a solution of phosphino)-9,9-dimercaptodibenzopyran (77.7 mg '0.13 mmol) in dioxane (1 mL), followed by the addition of bis(diphenylmethyleneacetone)dipalladium (0) (615 mg, 〇〇7 mmol) 'and the resulting solution was heated at 90 ° C for 18 hours. The mixture was cooled to room temperature and diluted with dioxane and water. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting eluting elut elut elut elut elut elut elut 2-Methyl-propyl)-lH-π ratio &lt;^-s-ylaminoamino]-2-methyl-2H-d-Chyle-3-(156 mg, 59%). Purification of 2-(6-t-butyl-8-fluoro-1. oxy oxazine _ 2(1H)-yl)-6-(4,4,5,5-tetramethyl) acetate with argon -1,3,2-dioxaboroin-2-yl)benzyl ester (282 mg, 0.57 mmol), 6-gas-4-(1-(2-hydroxy-2-methylpropyl)-iH -mouth ratio -sodium-3-ylamino)-2-methylpyridazin-3(2H)-one (100 mg, 0.34 mmol), acid clock (178 mg, 0.84 mmol) and dicyclohexyl (2 ',4',6,-Triisopropylbiphenyl-2-yl)phosphine (16.0 mg, 0.03 mmol) in butanol (4 ml) 157475.doc •297· 201211039 and water (1 mL) Then, (bis[diphenylmethyleneacetone]dipalladium) (9.66 11^, 0, 02 111111〇1) was added, and it was at 100. (The solution was heated for 2 hours. The resulting mixture was cooled, poured into a saturated solution of ammonium sulphate and extracted with di-methane (2×100 mL). The layers were separated and dried over magnesium sulfate. The residue was dissolved in dioxo (10 mL) and treated with a EtOAc solution (5 mL, 2.0 M) and the mixture was stirred overnight at room temperature. In an ammonium solution, the mixture was extracted with hydrazine dioxane (2 x 15 mL). The layers were separated and the organic phase was dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. Purification of the residue from 1% to EtOAc / EtOAc (methanol) [l-(2-Hydroxy-2-indolyl-propyl)_1H-pyrazole-3-ylamino]-1-methyl-6-oxirane-1,6-dihydro-pyridazinyl Phenyl)-2H-phthalazin-1-one (119 mg, 60%): MP 165-170. (: ; NMR (300 MHz, DMSO-^6) δ ppm 0.91-1.13 (m, 6 Η) 1.38 (s, 8 Η) 3.16-3.36 (m, 2 Η) 3.91 (s, 2 Η) 4.3 5-4.65 (m, 4 Η) 6.20 (d, /=2.27 Hz, 1 H) 7.28-7.64 (m, 4 H) 7.75 (d, J=13.22 Hz, 1 H) 7.82- 7'99 (m, 2 H) 8.51 (d, *7 = 2.27 Hz, 1 H) 9.24 (s, 1 H) Preparation 1-71 Example 71 157475.doc 298- 201211039

Use the ship-inferior procedure described for compound I-15, but with 6-chloro-2-indolyl-4-(Γ·methyl_1', 2, 3', 4', 5|, 6| -hexahydro-[34 L,4]bipyridin-6-ylamino)-2indole-pyridazin-3-one instead of the 6-gas in the step 11_?田#

Milk 2-methyl-4-(5-morpholin-4-carbonyl)amino)-6-sideoxy-U6-dihydro, continuous noise _3_yl]-phenyl} small side oxy group 1,2-monohydro-isoquinolin-6-yl)-2-methyl-propanenitrile gave the final product as a pale yellow powder. (M+H)+=634 m/e, NMR (300 MHz, chloroform-ί/) δ ppm 1.81 (s,6 Η) 1.82-1.90 (m, 4 η) 2.02-2.22 (m, 2 Η) 2.36 (s, 3 Η) 2.41-2.60 (m, 1 jj) 2.91-3.12 (m, 2 H) 3.91 (s, 3 H) 3.96-4.09 (m, 1 H) 4.23-4.49 (m, 2 H) 6.61 (dd, /-7.55, 1.89 Hz, 1 H) 6.91 (d, ^=8.31 Hz, 1 H) 7.21 (dd, 7=12.09, 1.89 Hz, 1 H) 7.35 (d, /=7.55 Hz, 1 H 7.42 (dd, /=7.74, 1.32 Hz, 1 H) 7.50-7.55 (mj 2 H) 7.59 (t, J-7.74 Hz, 1 H) 7.67 (dd, 7=7.93, 1.51 Hz, 1 H) 8.23 (d, •7=2.27 Hz, 1 H) 8.28 (s,1 H) 8.62 (s,1 H). Preparation 1-72 Example 72 I57475.doc •299- 201211039

Ο Use the general procedure described for compounds 1-15, but with 4-(5-azetidin-1-ylmethyl-1-indenyl-1H-d ratio. sit-3-ylamino) -6-Chloro-2-indenyl-2H-pyridazin-3-one in place of 6-gas-2-methyl-4-(5-morpholin-4-carbonyl)pyridin-2-ylamine in Step 11 Preparation of 2-(2-{3-[5-(5-azetidin-1-ylmethyl-1-indenyl-1H-.biazole) by pyridazine-3(2H)-one 3-aminoamino)-1-indolyl-6-tertiaryoxy-1,6-diaza-°Cheng-Qin-3-yl]-2-fluorenyl-phenyl}-8-gas-1 -Sideoxy-1,2-di-miso-iso-salt-6-yl)-2-indolyl-propanol' gave 471 mg of the final product as an off-white powder. (M+H)+=609 m/e, NMR (300 MHz, chloroform δ ppm 1.81 (s, 6 Η) 2.12 (five peaks, J=7.20 Hz, 2H) 3.27 (t, J=7.0 Hz, 4 H) 3.55 (s, 2 H) 3.81 (s, 3 H) 3.88 (s, 3 H) 4.03-4.19 (m, 1 H) 4.22-4.44 (m, 2 H) 5.94 (s, 1 H) 6.61 ( Dds /=7.36, 2.08 Hz, 1 H) 7.21 (dd, /=12.09, 1.89 Hz, 1 H) 7.35 (d, J=7.55 Hz, 1 H) 7.41 (dd, J=7.74, 1.32 Hz, 1 H 7.52 (d, J=1.51 Hz, 1 H) 7.56 (t, 7=7.74 Hz, 1 H) 7.65 (dd, •7=7.55, 1.51 Hz, 1 H) 7.82 (s,1 H) 7_91 (s , 1 H) ° Preparation 1-73 Example 73 157475.doc 300- 201211039

Ο F

The general procedure described for compounds 1-15 is used, but with 4_[5_(2_cycloheptane-1-yl-1,1-dimethyl-ethoxypyridine-2-amino group]_6 _ gas, 2 methyl-2 oxime-pyridazin-3-one instead of 6_chloro_2_indolyl_4_(5-morpholine 4-carbonylbi-2-ylamino)pyridazine in step U 3(2Η)_ketone to prepare 2-[2-(3-丨5吋5

(2-azetidin-1-yl-1, ι-didecyl-ethoxy)-pyridylamine oxime] 1-methyl-6-o-oxy-1,6-dihydro-indole Pyrazin-3-yl}-2-hydroxymethyl-phenyl)_8 Fluor-1-oneoxy-1,2-dihydro-isoquinoline-6-yl]_2-methyl-propionitrile. The resulting Suzuki product was subjected to the residue synthesis step 12 to give 143 mg of the final product as a pale yellow powder. (M+H)+=664 m/e, NMR (300 MHz, gas-like 〇f) δ ppm 1.24 (s,6 Η) 1.81 (s,6 Η) 2 12 (five peaks, J=6.80 Hz , 2 H) 2.59 (s, 2 H) 3.35 (t, /=6 99 Hz, 4 H) 3.91 (s, 3 H) 3.95-4.06 (m, 1 H) 4.25-4.44 (m, 2 H) 6 61 (dd, /=7.37, 2.08 Hz, 1 H) 6.89 (d, /=8.69 Hz, 1 H) 7 21 (dd, /=12.28, 1.70 Hz, 1 H) 7.33 (dd, /=8.69, 2.64 Hz, 2 H) 7.34 (d, 7=7.18 Hz, 1 H) 7.42 (dd, 7=7.74, 1.32 Hz, 1 H) 7.53 (d, “7=1.89 Hz, 1 H) 7.59 (t, J= 7.74 Hz, 1 H) 7.68 (dd J=7.93, 1.51 Hz, 1 H) 8.08 (d, 7=2.64 Hz, 1 H) 8.27 (s 1 H) 8.55 (s, 1 H). Preparation 1-74 Example 74 157475.doc 201211039

Use the general procedure described for compound 15, but with 6-chloro-2-indolyl-4-(5-methyl-4,5,6,7-tetrahydro-pyrazolo[i,5-a]pyridin Pyridazine-6-yl-2-mercapto-4-(5-morpholin-4-carbonyl)pyridin-2-ylamino)pyridazine -3(2H)-one to prepare 2-(8-fluoro-2-{2-hydroxymethyl-3-indole-indolyl-5-(5-fluorenyl-4,5,6,7-tetrahydro) -pyrazolo[i,5-a]pyrazin-2-ylamino)-6-o-oxy-1,6-dihydro-pyridazin-3-yl]-phenyl}-1-side oxygen Base-1,2-dihydro-isoquinolin-6-yl)-2-indolyl-propanenitrile gave 29 mg of the final product as a pale yellow powder. (M+H).=595 m/e ' 4 NMR (300 MHz, chloroform-d) δ ppm 1.8〇(s, 6 Η) 2.49 (s, 3 Η) 2.90 (t, 7=5.70 Hz, 2 H 3.61 (s, 2 H) 3.88 (s,3 H) 4.04-4.11 (m,1 H) 4.10 (t, 7=5.70 Hz, 2 H) 4.24-4.42 (m,2 H) 5.78 (s,1 H) 6.61 (dd, "7=7.37, 2.08 Hz, 1 H) 7.21 (dd, "7=12.09, 1.89 Hz, 1 Η) 7·34 (d, J=7.55 Hz, 1 H) 7.40 (dd, /=7.74, 1.32 Hz, 1 H) 7.52 (d, 7=1.89 Hz, 1 H) 7.55 (t, J=7.93 Hz, 1 H) 7.65 (dd, 7=7.93, 1.51 Hz, 1 jj) 7.84 ( s, 1 H) 7.98 (s, 1 H). Preparation 1-75 Example 75 157475.doc • 302- 201211039

teN

〇 ‘ o' F

The general procedure described for compound I-15 was used but with 6-(6-chloro-2-indolyl-3-oxo-2,3-dihydrooxazin-4-ylamino)-N , N-dimethyl-nicotine decylamine is substituted for 6-gas-2-mercapto-4-(5-morpholin-4-carbonyl)pyridin-2-ylamino)pyridazine-3 in step 11. 2H)-ketone to prepare 6-(6-{3-[6-(cyano-dimercapto-methyl)-8-fluoro-1-o-oxy-1H-isoquinolin-2-yl]- 2-Hydroxymethyl-phenyl}-2-methyl-3-oxo-2,3-dihydro-indol-4-ylamino)-N,N-dimethyl-in the amine 246 mg of the final product were obtained as a white powder. (M+H)+=608 m/e &gt; !H NMR (300 MHz, chloroform δ ppm 1.80 (s, 6 Η) 3.11 (s, 6 H) 3.85-3.91 (m, 1 H) 3.92 (s, 3 H) 4.26-4.46 (m, 2 H) 6.62 (dd, 7=7.55, 1.89 Hz, 1 H) 6.98 (d, /=8.69 Hz, 1 H) 7.21 (dd, J=12.28, 1.70 Hz, 1 H) 7.34 (d, 7=7.55 Hz, 1 H) 7.42 (m, 1 H) 7.53 (d, J=1.51 Hz, 1 H) 7.60 (t, /=7.74 Hz, 1 H) 7.65-7.72 (m , 1 H) 7.79 (dd, /=8.69, 2.27 Hz, 1 H) 8.44 (s,1 H) 8.47 (d, J=2.27 Hz, 1 H) 8.71 (s,1 H) 〇Preparation 1-76 Example 76

157475.doc • 303 · 201211039 Use the general procedure described for compounds 1-15, but with 6_gas_2_methyl_ 4-[5-((S)-l-indenylpyridinium_2_ Substituting for the 6-gas-2-mercapto-4-(5-morpholin-4-carbonyl)pyridin-2-yl group in Step 11 with a pyridine-based 2-amino group]_2H-pyridazine-3-yl ketone Preparation of 2-[8-fluoro-2-(2-hydroxymethyl-3-{l-fluorenyl-5-[5-((s)-i-) by amino)pyridazine-3(2H)-one Mercapto-pyrrolidin-2-yl)pyridin-2-ylamino]-6-hydroxyl-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-yloxy -1,2-Dihydro-isoquinoline-6-yl]-2-mercapto-propanenitrile gave 107 mg of the final product as a white powder. (M+H)+=620 m/e &gt; !H NMR (300 MHz, gas-d) δ ppm 1.65-1.79 (m, 1 H), 1.80 (s 3 H) 1.81-2.06 (m, 3 H) 2.17 (d, ^=189 Hz, 3 H) 2.23-2.37 (m, 2 H) 2.99-3.11 (m, 1 H) 3.18-3.31 (mj i H) 3.91 (s, 3 H) 3.96-4.09 (m, 1 H) 4.26-4.44 (ms 2 H) 6.61 (dd, /=7.37, 2.08 Hz, 1 H) 6.95 (d, •==8.31 Hz, 1 H) 7.21 (dd, /=12.46, 1.89 Hz, 1 H) 7.35 (d, •7=7.55 Hz, 1 H) 7.42 (dd, “7=7.93, 1.13 Hz, 1 H) 7.52 (d, J=l.S9 Hz, 1 H) 7.58 (t , 7=7.74 Hz, 1 H) 7.65-7.73 (m, 2 H) 8.24-8.28 (m,1 H) 8.30 (s,1 H) 8.67 (s,1 H). Preparation 1-77 Example 77 157475.doc •304· 201211039

The general procedure described for the compound ϊ-15 was used, but with 6-gas-2-methyl-4-[5_((S)-l-methyl 4 rryryl-3-yl) "pyridin-2-1" The aminoamino]-2Η-pyridazine_3_ ketone replaces 6-chloro-2-methyl_4_(5-morpholine-4-carbonyl)pyridin-2-ylamino)pyridazine-3 in step 11. )-ketone to prepare 2-[8-fluoro-2-(2-hydroxyindenyl-3-(3-(1-s)-methyl-5-[5-((s:m-methyl-pyrrolidine)-3-yl) _pyridine_2_ylamino]6_sideoxy_1,6-dihydro-'pyridazine-3-ylbuphenyl)-1_sideoxy-1,2-dihydro-isoquinoline _ 6_基]_2-Methyl-C., the final product (M+H)+=620 m/e ' NMR (300 MHz, gas-like, δ ppm 丄8ι ( s, 6 Η) 1.82-1.91 (mj ! H) 2.29-2.40 (m, 1 H) 2.42 (s, 3 H) 2.47-2.52 (m5 1 H) 2.63-2.82 (m, 2 H) 2.9l-3 .〇2 (m&gt; { H) 3.31-3.40 (m,1H) 3 9〇(s,3 H) 4 23 4 4 (, "/=7.55, 1.89 Hz, 1 H) 6.92 (d, /=8.31 Hz,} H) 7 21 (dd, 7=12.09, 1.89 Hz, 1 H) 7.35 (d5 J=7.18 HZj 1 H) 7 42 (dd, J=7.74, 1.32 Hz, 1 H) 7.52 (d5 J= 1.51 Hz, 1 H) 7 54 7-65 (m, 2 H) 7.65-7.71 (m, 1 H) 8.25 (d, J=: 2.64 Hz 1 m 8.28 (s, 1 h) 8.63 (s, i H ), , ) 157475.doc 201211039

Process E

This example illustrates "2-[2-(3-{5-[5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-°-pyridin-2- Amino]-1-methyl-6-o-oxy-1,6-dihydro-pyridazin-3-yl}-2-hydroxyindolyl-phenyl)-8-fluoro-1-yloxy Synthesis of -1,2,3,4-tetrahydro-isoindole-6-yl]-2-methyl-propion. Step 1 - Preparation of 6,8-difluoro-3,4-dihydro-2H-isoquinolin-1-one

F 157475.doc -306- 201211039 In a 1 〇〇〇 ml three-necked round bottom flask equipped with an overhead stirrer, sequentially feed 5,7--fluoro*'2,3-dihydro-1H-indole-1 -ketone (10 g, 59.4 mmol), anhydrous methylene chloride (100 ml) and methanesulfonic acid (71·3 m b 1.1 mol) »cooling the reaction to 0 ° C (ice bath) and over 20 minutes To this was added sodium azide (5.41 g, 83.2 mmol) in four equal portions. Here. (: stir the reaction for 2 hours, then pick up

Add 20°/ for 30 minutes under severe disturbance. Aqueous sodium hydroxide solution (175 ml). After the addition was completed, the mixture was transferred to a separatory funnel, and the di-methane phase was separated. This material was shaken together with an equal volume of a 5 〇% dilute brine solution. The organic phase was collected and the aqueous phase was back extracted with dioxane (2 x 80 mL). The organic phase was combined, dried (MgSO4) filtered and concentrated in vacuo. The crude residue was purified by EtOAc EtOAc (EtOAc) elute (m+h)+= 184 m/e. Step 2. Preparation of 2-(8-fluoro-1-oxo-1,2,3,4-tetrahydro-isoquinoline-6(6)- 2-indolyl-propanenitrile

To a solution containing 6,8-difluoro-3,4-dihydro-2-indole-isoquinoline-indole-one g, 21.8 mmol) and isobutyronitrile (6.04 g, 87·4 mmol) in anhydrous tetrahydrofuran (45 ml a solution of the solution in the solution was added with a solution of potassium bis(trim-decylalkyl)amine (50.4 ml, 〇_91 Μ in tetrahydrofuran), and the mixture was placed in an oil bath 157475.doc •307· 201211039 and heated To 70. (: When heating, obtain a red _ standard color spoon solution in 5 minutes. After 1 hour at 70 ° C 'addition of bis (tridecyl decyl) amination (5 ml, 0.91 M), and Continue stirring for another 30 minutes. Cool the flask to ambient temperature' and float the reaction with water (125 ml). Add ethyl acetate (1 mL) and transfer the material to a sep. funnel. The aqueous phase was back-extracted with ethyl acetate (2×70 ml). The combined organic phases were filtered and dried in vacuo. The residue was purified by silica gel chromatography to give a semi-pure fraction ( 710 mg 'purity of 33%) and pure product (316 mg) as a white powder. (M+H)+= 233 m/e 〇 Step 3. Preparation 2-[2-(3-Bromo-2-carbamimido-phenyl)-8-fluoro-1-oxooxy, 2,3,4-tetrahydro-isoquinolin-6-yl]-2- Methyl-propionitrile

This reaction was carried out under conditions similar to those described in Step 10 of Example 1-1 5 (Scheme D). After the treatment, the product was purified by gel electrophoresis using a gradient elution of 100% dioxane to 1% methanol/methylene chloride. This gave the desired product (278 mg) as a pale yellow solid. (M+H)+=415/417 m/e. Step 4. Preparation of 2-[2-(3-{5-[5-(2-azetidin-1-yl-1,1-diindolyl-ethoxyl 157475.doc-308- 201211039 base) -pyridin-2-ylamino]-1-methyl-6-yloxydiazepine-Qin-3-yl}-2-thiol-phenyl)-8-l-oxyl- 1,2,3,4-tetrayl]-2-mercapto-propanenitrile

This reaction was carried out under conditions similar to those described in Step 11 of Examples 1-15 (Scheme D), but using 4-[5-(2-azetidin-1-yl-1,1-dimethyl) _-ethoxy)-pyridine·2·ylamino]-6- ox-2-mercapto-2H-indol-3-one instead of 6-chloro*2_methyl-4-[5-(morpholine) 4-carbonyl)-pyridin-2-ylamino]-2Η-pyridazin-3-one. After the treatment, the product was purified by dissolving with a gradient of 100% dichloromethane to 1% methanol/diqimethane. This gave the desired product (172 mg) as a pale-brown solid. (M+H)+= 664 m/e. Preparation 1-78 Example 78 Step 5 · Preparation of 2-[2-(3-{5-[5-(2-氦1 heterocyclobutan-1-yl-1,1-didecyl-ethoxy) -°bipyridin-2-ylamino]-1-indolyl-6-sideoxy-oxime, 6-dihydro-pyridazine_3_yl}-2-hydroxyindolyl-phenyl)-8-fluoro -1-Sideoxy_ι,2,3,4_tetrahydro-isoquinolin-6-yl]-2-indolyl-propanenitrile 157475.doc -309- 201211039

The reaction was carried out under conditions similar to those described in Step 12 of Example I-15 (Scheme D). After treatment, the product was purified by gel electrophoresis using a gradient of 3% to 14% decyl alcohol / dimethyl alcohol. This material was then crystallized from EtOAc (EtOAc) elute (M+H)+=666 m/e. 'H NMR (300 MHz, chloroform δ ppm 1.23 (s, 6 Η) 1.76 (s, 6 Η) 2.11 (five peaks, •/=6.99 Ηζ, 2 Η) 2.58 (s, 2 Η) 3.12 (dt, /=16.15, 4.77 Hz, 1 H) 3.27 (t, J=7.0 Hz, 4 H) 3.36-3.45 (m, 1 H) 3.90 (s, 3 H) 3.93-4.16 (m,3 H) 4.34-4.69 (m, 2 H) 6.89 (d, /=8.69 Hz, 1 H) 7.14 (dd, 7=11.71, 1.51 Hz, 1 H) 7.25 (s, 1 H) 7.32 (dd, J=8.69, 2.64 Hz, 1 H) 7.37-7.44 (m, 1 H) 7.47-7.64 (m, 2 H) 8.07 (d, J=2.64 Hz, 1 H) 8.26 (s, 1 H) 8_52 (s, 1 H). Preparation 1 -79 Example 79 Preparation of 2-(8-fluoro-2-{2-hydroxyindolyl-3-[l-methyl-5-(5-oxetan-3-yl-4,5,6, 7-tetrahydro-. ratio. sit and [1,5-a] ° than 嗓-2-ylamino)-6-sideoxy-1,6-dihydro-pyridazin-3-yl]- stupid }}-1-sidedoxy-1,2-dihydro-isoquinolin-6-yl)_ 2-indolyl-propion 157475.doc -310- 201211039

F

6-Chloro-2-methyl-4-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[l,5-a]% azine-2 -ylamino)-pyridazine_3(2H)-one ("65 mg ' 194 μηιοί), bis (pinadol) shed (54.1 mg ' 213 μπιοί) and as described in % 6〇 Potassium acetate (57_〇mg, 581 μπιοί) was suspended in dioxin (9 ml). The reaction mixture was degassed under the atmosphere. ^ PHOS (13.8 mg, 29.0 μπχοΐ) and palladium acetate (11) (2.17 mg, 9.68 μιηοΐ) were added and the reaction mixture was mixed under an argon atmosphere for 45 minutes at 10 ° C (external temperature). LCMS (in methanol) showed some conversion to a face acid (M+1 = 347) and some converted to the desired 2-methyl- 4-(5-oxetan-3-yl-4,5 6,6-tetrahydro-pyrazolopyrazine-2-aminocarbyl)_2H-pyridazin-3-one. Heat down to 8 °C. The flask was taken out of the heating bath and stirring was continued. Addition of 2-(2-(3-bromo-2-carboxyphenyl)-8-fluoro-1-yloxy-1,2-dihydroisoquinolin-6-yl)-2-methyl Propionitrile (2 mg of '80 mg, 194 μηιοί) of 2 mg of dioxane and potassium carbonate (80.3 mg, 581 μmol) was prepared as described in Example 15 followed by the addition of 1 mL of H20. Tricyclohexylphosphine (5·43 mg' 19.4 μηιοί) and bis(dibenzylideneacetone)-palladium (〇) (5.57 mg, 9.68 μηιοί) were added. The reaction mixture was heated at 80 ° C for 1.5 hours with vigorous stirring. The crude reaction was poured with EtOAc (EtOAc)EtOAc. The combined organic extracts were washed with brine, 157475.doc -311 - 201211039 and dried over MgSO4. The crude material was purified by flash chromatography (EtOAc, EtOAc (EtOAc:EtOAc) Methyl_5_(5_(oxetan-3-yl)_4,5,6,7-tetrahydropyrazolo[l,5-a].pyrazine-2-ylamino)-6- The pendant oxy-1,6-dihydropyridazin-3-yl)phenyl)-1-yloxy-1,2-dihydroisoquinolin-6-yl)-2-methylpropanenitrile. In a 25 mL round bottom flask, 2-(8-fluoro-2-(2-methylindolyl-3-(1-methyl-5-(5-(oxetidin-3-yl))-4, 5,6,7-tetrahydrogen. Compared with 嗤[l,5-a]° 嗓-2-ylamino)-6-sideoxy-1,6-dihydropyridazin-3-yl)benzene ))-1-yloxy-i,2-dihydroisoquinolin-6-yl)-2-mercaptopropionitrile (90 mg, 142 μιηοΐ) with anhydrous CHzCl 2 ml) and anhydrous MeOH (0.5 mL ) Combine 'to get a light yellow solution. Cool the solution to 〇 °C. Sodium borohydride (9.66 mg, 255 μιηοΐ) was added. The reaction mixture was stirred at 〇 ° C for 40 minutes. The reaction was completed by LCMS analysis. Quenched with saturated NH4C1. The reaction mixture was poured into EtOAc (EtOAc)EtOAc. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc, 24 g, 0% to 3% MeOH). The pure fractions were concentrated to give EtOAc (EtOAc). (M+H)+=637 m/e. NMR (300 MHz, MV-ώ〇δ ppm 1.81 (s,6 Η) 2.90 (t, •7=5.48 Ηζ, 2 Η) 3.55-3.71 (m,2 Η) 3.77-3.86 (m,1 Η) 3.89 (s, 3 Η) 4.17 (t, J=5.48 Hz, 2 Η) 4.26-4.42 (m, 2 Η) 4.66-4.87 (m, 4 Η) 5.83 (s, 1 Η) 6.62 (dd, /= 7.55, 1.89 Hz, 1 H) 7.22 (dd, 7=12.28, 1.70 Hz, 1 H) 7.34 (d, 7=7.18 Hz, 1 H) 7.41 (dd, J=7.74, 1.32 Hz, 1 H) 7.50- 7.61 (m, 2 H) 7.63- 157475.doc -312- 201211039 7.72 (m,1 Η) 7.85 (s,1 Η) 7.95 (s,i η). Preparation 1-80 Example 80 Preparation 6-Third -8-gas (4) methyl-3*methyl oxetane-3-yl-1,,2,,3',4,,5,6,-hexahydro-[3,41 Bipyridine _6_ylamino)6_ oxo-1,6-dihydro-d--3-yl]-phenyl b 2Η_呔嗓_丨_网

Step 1. To 6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridine-2-ylamino)pyridazine-3(2Η)-one (639 mg, 2.00 mmol, Acetic acid (360 mg '343 μΐ, 5.99 mmol, 3.0 eq.) was added to a solution of 1.00 eq. and oxetane _3 ketone (288 mg ' 4.00 mmol, 2.0 eq.) in thf (1 〇mi). The reaction mixture was stirred at 5 5 C for 1 hour under N 2 . Sodium triethoxide borohydride (847 mg, 4.00 mmol, 2.0 eq.) was then added at 65. The mixture was stirred for 2 hours under the arm. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between DCM and sat. NaHC. The layers were separated&apos; and the organic layer was washed with water. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. Purification of the crude material by flash chromatography (24 g, 〇% to 40% (60:10:1 DCM: MeOH:NH4OH)/DCM gradient) yield 157475.doc -313· 201211039 to 6_gas -2-methyl-4-(l,-oxetan-3-yl-l,,2,,3,,4,,5,6,-hexahydro-[3,4,] Pyridyl-6-ylamino) 2H-pyridazin-3-one (453 mg, 60%). Observed by LC/MS-ESI [M+H]+ 376. NMR (in CDC13) was consistent with the desired product. Step 2. In a 50 mL tube, 6-gas-2·methyl-4-(5-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-yl Amino)pyridazin-3(2H)-one (120 mg, 319 μιηοΐ) and 2-(6-t-butyl-8-gas-1-oxooxypyrazine-2(111)-yl) _ 6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzoquinone (271 mg, 383 μπιοί) combined with Bu〇H (4 ml) 'Get an orange solution. Add 1 mL of water. Purified with argon. X-PHOS (15.2 mg, 31.9 μιηοΐ) and tripotassium phytate (136 mg ''639 μιηοΐ) were added. Argon was bubbled through for 5 minutes. Bis(diphenylmethyleneacetone)_palladium (〇) (9.18 mg, 16 〇 μπιοί) was added and the reaction mixture was placed under an argon atmosphere at u 〇. The clams were warmed in an oil bath for 1.5 hours. Analysis of 6-chloro-2-indolyl-4-(5-(1-(oxetan-3-yl)pyr-4-yl)&quot;biti-2-ylamino)哒 by LCMS There is no residue in the azine-3(2Η)-one. Two major products were observed by LCMS: the acetamidine product and the deacetylated product. The reaction mixture was allowed to cool to room temperature overnight and concentrated to a small volume. The reaction mixture was poured into EtOAc (3×75 mL). The organic layer was dried over NazSCU and concentrated in vacuo. The crude material was purified by flash chromatography (yield: 24 g, DCM containing 1% to 6% MesH). The pure acetamidine product and the deacetylated product were combined with the mixed solvent and concentrated to give a mixture of 162 mg. 2-(6-Tertiary -8_ gas-oxyloxyacetate is blown to °-2(1H)-yl)-6-(1-indolyl-5-(5-(1-(oxa)) Cyclobutane _3_ base) I57475.doc -314- 201211039 0 bottom bite-4-yl) ° bite-2-ylamino)-6-sideoxy-1,6-dihydrogen 3-yl)benzoquinone (162 mg ' 229 μπιοί ' 1.00 equivalent) and 6-t-butyl-3-8-fluoro-2-(2-(hydroxymethyl)-3-(1_fluorenyl_5_( 5_(1•(oxe-butane-3-yl)piperidin-4-yl) ratio: 1,4-ethylamino)-6-o-oxy-1,6-dihydropyridazine-3- This mixture of pyridazine-1(2Η)-one (152 mg '229 μιηοΐ) was dissolved in 8 mL of THF. Add 2 mL of 1 N NaOH. The reaction was warmed at 50 °C for 6 hours' followed by warming at 60 C for 18 hours. The reaction mixture was poured into 1 mL mL H.sub.2 and extracted with Et.sub. The combined organic extracts were washed with brine and dried over MgSO 4 and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc, EtOAc (EtOAc: EtOAc: EtOAc) The desired product (78 mg). (M+H)+=666 m/e. 4 NMR (300 MHz, gas δ δ ppm 1.43 (s, 9 Η) 1.58 (br. s., 1 H) 1.72-2.06 (m, 3 H) 2.89 (br. s., 1 H) 3.75-4.09 ( m, 4 H) 4.43 (d, 7=6.80 Hz, 2 H) 4.69 (d, «7=6.42 Hz, 3 H) 6.92 (d, */=8.31 Hz, 1 H) 7.42-7.62 (m, 5 H) 7.63-7.71 (m, 1 H) 8.17-8.35 (m, 3 H) 8.61 (s, 1 H) Preparation 1-81 Example 81 Preparation of 6-t-butyl _8_fluoro 2 gas 2 - hydroxy曱基_3_[丨_曱-yloxacyclobutane-3-yl_1,,21,3',41,51,6,_hexahydro-[3,4,]-linked (1 to alkidine_6 _ylamino)_6_ pendant oxy-1,6-dihydrodaazine _3_yl]-phenyl b 2H-pyridazine 嗣 嗣 157475.doc •315· 201211039

Prepared by a procedure similar to the example, but using 6_gas 0 gas-2-methyl_4 (1,_oxaindole-3-yl_ι,, 2,, 3, 4, 5 ,,6,_ hexahydro-[3 4Ί,?Μ * ▲ ,] hydrazinium-6-ylamino)-2Η-pyridazine_3_one instead of 6_chloro_2_methyl_4 1(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1&gt;5-a]pyrazine_2-ylamino)pyridazine_3(2η)_ _ 'The desired product (173 mg) was obtained as a white powder. (Μ+Η)+=676 m/e. 4 NMR (300 ΜΗζ, gas-d) δ ppm 1.43-2.10 (multiple peaks and overlapping singlet, 14 Η) 2.54 (d, "/=7.18 Hz, 1 Η) 2.91 (d, /=9.44 Hz, 2 H) 3.55 (br. s., 1 H) 3.91 (s, 3 H) 4.01 (dd, J=10.20, 4.15 Hz, 1 H) 4.20-4.50 (m, 2 H) 4.69 (d and m, /= 6.42 Hz, 3 H) 6.62 (dd, 7=7.36, 2.08 Hz, 1 H) 6.92 (d, /=8.69 Hz, 1 H) 7.22 (dd,*/=12.46,1.89 Hz,1 H) 7.35 (d , *7=7.55 Hz, 1 H) 7.42 (dd, J=7.74, 1.32 Hz, 1 H) 7.49-7.64 (m, 3 H) 7.65-7.74 (m, 1 H) 8.17-8.33 (m, 2 H ) 8.63 (s, 1 H). Preparation 1-82 Example 82 Preparation of 6-t-butyl-2-{3-[5-(5-ethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-&amp;] °Bipyrimidin-2-ylamino)-1-methyl-6-o-oxyl,6-dihydro-°°°qin-3-yl]-2·methyl-based}-8 - Lose -2H-0 too. Qin-1-嗣 157475.doc •316- 201211039

Mg). (M+H)+ but replace 599 m/e in step 5 with ethylamine. H NMR (3〇〇mHz, gas-d-d) δ ppm 1.21 (t, •7=7.18 Hz, 3 Η) 1.43 (s,9 H) 2 67 (d, J=6 42 Hz, 2 H) 2 99 (br. s., 2 H) 3.70 (br. s., 2 H) 3.88 (s, 3 H) 4.02 (t, "7=6.99 Hz, 1 H) 4.15 (br. s., 2 H) 4.40 (d, "7=6.80 Hz, 2 H) 5.83 (s, 1 H) 7.41-7.59 (m, 4 H) 7.61-7.67 (m, 1 H) 7.81 (s, 1 H) 7.92 (s, 1 H) 8.28 (d, / = 2.64 Hz, 1 H) Preparation 1-83 Example 83 Preparation 2-(2-{3-[5-(5-ethyl- 4,5,6,7-tetrahydro-). Bisazo[i,5-a]° -2--2-ylamino)-1-methyl-6-sideoxy-i,6-dihydro-pyridazin-3-yl]-2-hydroxyl Methyl-phenyl}-8-fluoro-1-oxo-i,2-dihydro-isoquinolin-6-yl)-2-methyl-propanenitrile

Prepared by a procedure similar to that of Example 80, but using 6-chloro-4-(5-ethyl-4,5,6,7-tetrahydro-pyrazolo[l,5-a]»pyrazine-2-胺 ) _2 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 哒 475 475 475 475 475 475 475 475 475 475 475 475 475 475 _4,5,6,7_ tetrahydrogen ratio °[1'5-a]e than indole-2-ylamino)-indazinyl-3(2h)-one, which is obtained as a white powder Product (70 mg). (m+h)+=609 m/e. NMR (300 ΜΗζ, gas-c〇δ ppm 1.13.1.29 (m,3 Η) 1.57 (br. s·, 2 Η) 1.81 (s,7 Η) 2.67 (br. s·,1 η) 2.99 ( Br. s·,1 Η) 3.70 (br_ s.,1 H) 3.89 (s,3 H) 4.02-4.21 (m,3 H) 4.22-4.47 (m, 2 H) 5.81 (s, 1 H) 6.61 (dd, 7=7.36, 2.08 Hz, 1 H) 7.21 (dd, 7=12.09, 1.89 Hz, 1 H) 7.35 (d, J=7.i8 Hz, 1 H) 7.38-7.44 (m, 1 H) 7.49-7.60 (m, 2 H) 7.63-7.69 (m, 1 H) 7.83 (s, 1 H) 7.94 (s, 1 H). Preparation 1-84 Example 84

The general procedure described in Example 41 was used to prepare the third butyl-2-[3- using (1S,4S)_2,5-diazabicyclo[2.2.imnf acid tert-butyl(tetra)-demethylmethazine. (5-{5-[(lS,4S) small (2,5-diaza-bicyclo[2.2.1]hept-2-yl)methyl]" ratio. _6_Sideoxyanthracene, 6-dihydrogen+Qin-3-yl)-2-methyl-li-yl]Ifluoro-2H-pyrazine-1-one. Synthesis of the compound at the end of this compound (4) The 1 MNa〇M non-carbonic acid was used to remove the acetic acid 157475.doc-318-201211039 hydrazine protecting group, using THF as a solvent and heating at 60 ° C for two hours, followed by stirring at room temperature overnight. 1,1,1,3,3,3-hexafluoro-2-propanol removed BOC protecting group 'Use alcohol as solvent and heat in microwave reactor for 30 minutes at M (rc), at 150 °C After heating for an additional 45 minutes, after purification by chromatography using a gradient of DCM 5% to 25% methanol, 50 mg of the product as an off-white powder was obtained. iH nmr (300 MHz, DMS046) δ ppm 9.39 (s, 1 H) 8.49-8.56 (m, 2 H) 8.19-8.50 (m, 1 H) 7.88 (s, 1 H) 7.71-7.76 (m, 1 H) 7.54-7.61 (m, 1 H) 7.44-• 7.51 ( m,4 H) 4.56 (t,*7=5 .7 Hz,1 H) 4_42 (br. s.,2 H) 3.91 (s, 1 H) 3.77 (s, 3 H) 3.52-3.64 (m, 4 H) 3.06 (d, /=10.2

Hz, 1 H) 2.71 (d, "/=9.4 HZ, 2 H) 2.38 (d, "7=9.1 Hz, 1H) 1.72 (d, J = 10.2 Hz, 1 H) 1.44 (d, J = 7.6 Hz , 1 H) 1.38 (s, 9 H). MS: (M+H)+=637. Mp&gt; 25〇t. Preparation 1-85 Example 85

Prepared by a procedure similar to Example 41 but using 4-methyl-piperidin-4-ol

6-tert-{5-[5-(4-hydroxy-4-methyl-piperidin-1-ylindole-) obtained as a white solid as a white solid. Methyl-6-o-oxy-1,6-dihydro-pyridazine-3-157475.doc-319·201211039-based}-phenyl)-2H-phthalazin-1-one (83 mg). (M+H)+=654 m/e. NMR (300 MHz, chloroform-¢/) δ ppm 1.26 (s,3 Η) 1.43 (s,9 Η) 1.60 (d, "7=13.97 Hz, 4 H) 3.91 (single peak and overlapping multiplet, 4 H 4.43 (d, 7=7.18 Hz, 2 H) 6.94 (d, J=8.31 Hz, 1 H) 7.42-7.71 (m, 5 H) 8.23-8.34 (m, 3 H) 8.65 (s, 1 H) Prepare 1-86 Example 86

Prepared by a procedure similar to that of Example 56, but substituting ethyl 4-(6-nitro-pyridin-3-yl)-0 henazine-1-carboxylate for the hydrazine in the first step. Pyridine _ 3_ phenyl oxazine' gave 4-(6-{6-[3-(6-t-butyl-8- gas-1-yloxy-1H-pyridazine) as a yellow solid _基)_2_hydroxyindoleyl_phenyl]_2_mercapto_3_sideoxy-2,3-dihydro-pyridazine-4-ylamino}-pyridine-3-yl)-piperazine- Ethyl acetate (43 mg). (m+h)+=654 m/e. 4 NMR (400 MHz, chloroform-d) δ ppm 1.22 (t, J = 7.15 Hz, 3 H) 1.36 (s, 9 H) 3.10 (br. s.5 4 H) 3.66 (br. s.3 3 H) 3.83 (s, 3 H) 4.11 (q, J=7.11 Hz, 2 H) 4.29-4.30 (m,i H ) 4.35 (s, 2 H) 7.03 (d, J = 8.28 Hz, 1 H) 7.34-7.64 (m, 6 H) 8.00 (br. s., 1 H) 8.22 (d, J = 2.51 Hz, 157475. Doc - 320 - 201211039 1 H) 8.36 (s, 1 Η). Preparation 1-87

Process F

Preparation of 8-fluoro-6-(2-fluoro-1,1-dimethyl-ethyl)-2-(2-hydroxymethyl-3-{l-methyl&amp;_5矸5~(morpholine-4) -carbonyl-)pyridylamino]-6-oxo-1,6-dihydro-pyridazine 4~yl}-phenyl)_2H-isoquinoline step 2-(8-fluoro-1-side Preparation of 2-(8-fluoro-1-oxo-1,2-dihydroisoindole in a lye flask by oxy-1,2-dihydroisoquinolin-6-yl)-2-methylpropane A solution of quinoline-6-yl)-2. mercaptopropionitrile (I.77 g, 334 mm) in THF / toluene. The flask was cooled to _78 under A atmosphere. Hey. DiBAL-H (14 mL, 1 Μ, 157475.doc 14 -321 - 201211039 mmol) was added to the mixture via a syringe for about 1 Torr. The reaction mixture was stirred at -78 °C for 60 minutes, then warmed to 0 ° C and stirred for 1 hour. To the resulting solution were added 50 ml of 3 N HCl (aq) and 50 ml of EtOAc. The mixture was shaken and the EtOAc phase was collected and washed with 25 mL brine. Back extraction (2 x 40 ml EtOAc) in water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Only 344 mg of crude product was obtained. The product was crystallized from hot DCM / hexanes. The product was collected by filtration to give 280 mg of white crystals. (M+H)+=234 m/e. Step 2. Preparation of benzyl-2-mercaptopropan-2-yl)isoindole _ l(2H)-m 2-(8-fluoro-1-oxo-l,2-dihydroisoquinoline _6-yl)-2-mercaptopropanal (137! 1^, 587 4111 〇 1) was dissolved in 1 011 and cooled in an ice bath. To the resulting solution, NaBH4 (33 mg, 881 μιηοΐ) was added in one portion. The reaction mixture was stirred vigorously for 5 minutes&apos; then the cooling bath was removed and stirred for 3 liters. To the reaction mixture was added about 4 mL of 10% HCl and 40 mL of EtOAc. Shock the mixture and collect the jgt〇Ac phase. The organic phase is washed with an equal volume of water. The aqueous phase was back extracted with 2 x 30 mL EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. (M+H)+=23 6 m/e. Step 3·Injury 8-fluoro-6-(1-fluoromethylpropan-2-yl)isoindene-1 (Rain ketone will be 8-fluoro-6-(ι_hydroxy_2_methyl propyl _ 2_yl)isoquinoline 4 (2^·ketone mg. '485 μιηο1) was dissolved in DCM (anhydrous) and cooled to 78 C under argon. To this solution was added diethylaminosulfur trifluoride. (9〇^μηιοί) 'And stir the reaction for about 1 minute, then remove the cooling bath. Warm the reaction to ambient temperature and stir at this temperature for 2 hours. Add 25 ml to the reaction 157475.doc 201211039 mixture Water and 20 ml of DCM. The mixture was shaken and the organics were collected. The organics were washed with brine (25 mL). EtOAc (EtOAc) (2 trays, eluted with 4.5% MeOH / DCM) to afford crude product (yield: mp. [8-Fluoro-6-(2-fluoro-U1-dimethyl-ethyl)-1-yloxy-1H-isoquinolin-2-yl]-benzaldehyde 6,8-difluoro-3, 4-Dihydro-2H-isoquinolin-1-one in a 250 mL round bottom flask, 8_fluoro_6_(bufluoro-2-methyl) -2-yl)isoquinoline-1(2H)-one (92 mg, 388 μιηοΐ), 2-bromo-6-chlorobenzaldehyde (136 mg ' 620 μιη〇1) and potassium carbonate (107 mg,776 Μπιοί) in combination with DMSO (1 · 23 ml) to give a yellow suspension. The mixture was degassed with argon for 5 minutes. Copper iodide (1) (7) 9 mg, 13.1 μM, 388 μηηοΐ) was added and the mixture was placed under the armpit In the oil bath. The reaction mixture was heated to 110 ° C ' and stirred for 5 hours. The reaction was not completed by LCMS analysis. Additional 2-bromo-6-chlorobenzidine (7 〇 mg) was added. The reaction mixture was heated to 1 l ° ° C ' and allowed to mix for 3 hours' and then cooled to ambient temperature. The crude reaction mixture was filtered through a pad of Celite, and washed well with EtOAc. The combined mash and wash solution was added to a separatory funnel containing 25 ml of a 1:1 saturated NH4C1 dilute solution/water. The organic phase was collected and washed with an equal volume of brine. The aqueous phase was extracted (2 x 20 mL EtOAc). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by preparative EtOAc (2 EtOAc (EtOAc) elute =376 m/e. Example 87

Prepared by a procedure similar to that of Example 15 (Steps 11-12) but using 2-chloro-6-[8-fluoro-6-(2-fluoro-1,1-dimethyl-ethyl)-1-one Substituting _ 啥 _2 _ _ _ _ _ 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 替代 。 。 。 ratio. </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; (2_ via methyl_3-{1-indolyl_5-[5-(morpholin-4-carbonyl)-pyridin-2-ylamino]-6-sideoxy-oxime, 6-dihydrogen -pyridazine_3_yl}-phenyl)-2H-isoquinolin-1-one (43 mg). (M+H)+=657 m/e. NMR (300 MHz, gas-d) δ ppm 1·36 (s,3 Η) 1.43 (s,3 Η) 2.92-3.10 (m, 2 Η) 3.56-3.80 (m, 8 Η) 3.91 (s, 4 Η) 4.38 (d, «7=4.15 Hz, 2 Η) 6.57 (dd, "7=7.55, 1.89 Hz, 1 Η) 6.97-7.14 (m, 2 H) 7.25 (dd, /=10.39, 2.83 Hz , 2 H) 7.41 (dd, 7=7.74, 1.32 Hz, 1 H) 7.52-7.70 (m, 2 H) 7.77 (dd, /=8.31, 2.27 Hz, 1 H) 8.38-8.53 (m, 2 H) 8.70 (s, 1 H). Preparation 1-88 Example 88 Step 1. Preparation of 6-chloromethoxy-4-trimethyldecyl-anthracene 157475.doc •324- 201211039

Cl

Under an argon atmosphere, 4.0476 g of diisopropylamine distilled and 6 〇1 of tetrahydrofuran (Aldrich' anhydrous, no stabilizer) were placed in a two-necked round bottom flask. The mixture was cooled to -78 C, followed by the addition of about 2 mL of a hexane containing 2 〇 M butyl lithium. The mixture was placed in an ice bath for 2 G minutes, then cooled to _7 passages, and 2.8912 g of 3-chloro-6-methoxy-azine and 3.05 mL of chlorotrimethylnonane were added in 12 mL of tetrahydrofuran over 15 minutes. Solution. The mixture was stirred for 2 hours (dark red, then fading to yellow) and then quenched by the addition of i? The mixture was dissolved in ethyl acetate (3 mL), washed with 1×75 mL brine, dried over anhydrous sodium sulfate, filtered and evaporated. By silica gel chromatography (siHcyele 8〇 g column,

Cm (174 mL vol.) was applied to EtOAc (EtOAc: EtOAc) Step 2. Preparation of 6-gas-2-methyl-4-tridecylsulfonyl 2H-pyridazine-3-one and 6-fluoren-2-indolyl-4-trimethyldecylpyridazine-3 -顚! 157475.doc

X = CI, I 1.6068 g of 6-gas-3-decyloxy-4-trimethyldecyl-decazine and 40 mL of chloroform (Aldrich 'anhydrous pentene inhibitor) were placed in a round bottom flask. The mixture was vacuum purged 3 times with argon, followed by 5 mL of a gas mixture (reaction turned amber) containing 3 33 mL of iodine trisole • 325·201211039 decane. The flask was placed in a bath at 60 ° C and stirred for 2 hours, then 'cooled the mixture and the reaction mixture was dissolved in 450 mL of dichloromethane' with 1 x 200 mL containing 5 g of sodium thiosulfate and 3.6 g of K2HP〇4 The brine was washed with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, Silicid 40 (2.6 x 13.3 cm, 71 mL volume), and the crude product was purified by dioxo-acetic acid-acetic acid (90:10) to give 2.69 g. a yellow solid consisting of 6-chloro-4-trimethyl-stone-alkyl-2H-oxazin-3-one and 6-A-4-dimethyl-stone-alkyl-2H-indol-3-one : 3 mixture composition. This mixture was placed in a round bottom flask under argon. 5·48 § carbonate planer and 15 mL of dimethylformamide were added thereto. The mixture was cooled in an ice bath and 2.38 g of methyl iodide was added over 6 s. The cooling bath was removed and the mixture was stirred at room temperature. After 90 minutes, the mixture was dissolved in EtOAc (3 mL), EtOAc (EtOAc) On silicone (Silicycle 40 (2.6xl3 3 cm 71 mL body with dichlorodecane-ethyl acetate (98:2))

The crude product was purified by dissolving the sample in a solvent to give an off-white solid in the form of a 6:4 mixture of the compound.

Base)-benzaldehyde vinegar 157475.doc 326· 201211039

3.21 g of 2-(6-t-butyl-8-fluoro-1-oxo-1H-pyridazin-2-yl)-6-(4,4,5,5-tetradecyl-[ 1,3,2]diboron-2-yl)-benzoate, 2.06 g of sodium carbonate, 0.68 g of ditriphenylphosphine dipalladium and 1.99 g of 6-gas-2-mercapto-4- A 6:4 mixture of trimethylsulfonylalkyl-2H-pyridazin-3-one and 6-iodo-2-indolyl-4-trimethyldecyl-2H-pyridazin-3-one was placed in a round bottom flask. Then, 130 mL of dioxane (EM DriSolv)-water (10:1) was placed. The mixture was vacuum purged 5 times with argon, then placed in a bath at 95 ° C and stirred (mechanical). After 5.5 hours, the mixture was cooled, dissolved in ethyl acetate (350 mL) and washed with 1 X 75 mL brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and evaporated. By silica gel chromatography (Silicycle 120 g '3.5x21.5 cm '207 vol), applied to dichloromethane, dissolved in CH2C12-ethyl acetate (80:20), followed by silica gel chromatography (Silicycle 120) g, 3.5x21.5 cm, 207 vol), applied to a methane, and the crude product was purified by di-hexane-ethyl acetate (80:20) to give 2.5418 g (71 ° /.). A foamy product. Step 4. Preparation of 2-(5-bromo-1-methyl-6-oxooxy-1,6-dihydro-pyridazin-3-yl)-6-(6-t-butyl-8-acetate) Fluor-1-oneoxy-1H-pyridazin-2-yl)-benzidine

157475.doc -327· 201211039 2.54 g of acetic acid 2-(6-t-butyl_8_fluoro-丨_sideoxy-1Η^λazine·2_yl)-6-(1-methyl-6- Side oxy-5-trimethyldecyl-indenyl--dihydro-pyridazine-3-yl)-phenylmethyl ester, 5.51 g of potassium bromide, 4.55 g of potassium acetate were placed in a round bottom flask with a reflux condenser Then, put about 8 49 〇 8 to stink. The mixture was warmed while bromine was added. The mixture was stirred at room temperature for 2 minutes, then placed in a bath under 55 and stirred. Gently place the stopper on top of the reflux condenser to accommodate the bromine vapor. After 70 minutes, the mixture was cooled to room temperature and excess bromine was removed under a stream of nitrogen. The mixture was dissolved in 500 mL of dioxane, washed with 1 χΐ 5 〇 mL of brine containing 12 g of sodium hydrogen sulphate, with some exotherm, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By gelatin chromatography (Silicycle 120 g, 3.5 x 21.5 cm, 207 vol), applied to dichloromethane, dissolved in dioxane-ethyl acetate (80:20), followed by silica gel chromatography (SiUcycle 120 g, 3.5 x 21.5 cm, 207 vol), which was applied to dichloromethane, eluted with dioxane-ethyl acetate (8 〇: 2 〇) to give a white solid. The desired product (丨.91 g). Step 5, Preparation of acetic acid 6-t-butylfluoro-2-(2-methyl-methylmethyl 5-[5((lS,4S)-5-methyl-2,5-diaza-bicyclo[2] 2 ”heptyl]yl)_πpyrazine-2-ylamino]-6-oxooxy-1,6-dihydro-pyridazine_3_yl}_phenyl)·2Η•pyridazine_1_one 157475.doc 328· 201211039

5-((lS,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)pyrazin-2-amine (4-indolyl from Example 34) Preparation of 3,4,5,6-tetrahydro-2ΐί-[1,2']bipyrazine-5'-ylamine, 50 mg, 292 μιηοΐ), 2-(5-bromo-1- Methyl-6-o-oxy-1,6-dihydro-azin-3-yl)-6-(6-t-butylfluoro-1-one-oxy oxime-2(1Η)-yl) Benzoic acid (170 mg, 307 μιηοΐ), carbonated planing (286 mg, 877 μηιοί), xantphos (25 mg, 44 μηιοί), ginseng (diphenylmethyleneacetone) two (0) (2 0 mg, 22 μ mol) and 2° smoldering (3 mL) were combined in a microwave vial, degassed with argon and heated at 100 ° C for 18 hours. The crude reaction mixture was filtered through celite, concentrated and purified by chromatography using EtOAc EtOAc. The resulting residue (a mixture of the acetylated product and the deacetylated product) was dissolved in decyl alcohol. Potassium carbonate (61 mg, 441 μηιοί) was added and the reaction was heated at 4 °t for 1 hour. Water was added dropwise and the resulting mixture was stirred overnight at room temperature. The solid was collected by filtration. Purification by preparative tic (in DCM containing 1 〇〇 /0 methanol) gave the desired product as a yellow powder ( 丨 7 mg). (M+H)+=638 m/e. !H NMR (300 MHz, DMSO-ij?6) δ ppm 1.37 (s, 9 H) 1.66-1.92 (m, 2 H) 2.25 (s, 3 H) 2.78 (d, J=8.31 Hz, 1 H) 3.41 (d, ./=10.20 Hz, 2 H) 3.75 (s, 3 H) 4.28-4.58 (m, 4 H) 7.39- 157475.doc - 329- 201211039 7-55 (m, 3 Η) 7.68-7.79 (m5 2 Η) 7.85 (d, J=1.51 Hz, 1 H) 8.05 (s5 1 H) 8.35 (d, /=1.51 Hz, 1 H) 8.49 (d, /=2.27 Hz, 1 H) 9·34 (s, 1 h). Preparation 1-89 Example 89

The general procedure described for the compound Μ5 was used, but with 6-vapor-2-indolyl-4-[5-((R)-1-indolyl-pyrrolidin-3-yl)-pyridin-2-ylamino ]-2Η-pyridazine-3-oxime in place of 6-gas-2-methyl-4-(5-morpholin-4-carbonyl)pyridin-2-ylamino) phosphine _3 (2H) -ketone to prepare 2-[8-fluoro-2-(2-hydroxyindolyl-methyl-5-[5-((S)-l-f-yl-pyrrolidinyl))-pyridine-2 -ylamino]-6-hydroxyl_1,6_-nitrogen-Qinqin-3-yl}-phenyl)-1 -trioxy-1,2-diaza-isoindole_6- Benzyl-2-methyl-propionitrile gave 32 mg of the final product as a pale yellow powder. (M+H)+=620 m/e » Preparation 1-90 Example 90 Preparation of 6-t-butyl-8-fluoro-2-(2-hydroxymethylindolyl-6- pendantoxy-5-[ Γ-(2,2,2-Trifluoro-ethylhexahydro-[3,4,]bipyridin-6-ylamino]-1,6-dihydro-pyridazin-3-yl}-phenyl )-2H-pyridazin-1-one 157475.doc -330- 201211039

Cf3 to 6-t-butyl-8-fluoro1-2-(2-(fluorenyl)-3-(1-indolyl-6-o-oxy-5-(5-() Piperidin-4-yl)pyridin-2-ylamino)-1,6-dihydropyridazin-3-yl)phenyl)pyridazine-1(2H)-one (10 mg, 16.4 μπιοί) in DMF Potassium carbonate (6.8 mg, 49.2 μηιοί) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.8111^, 2.36 41, 16.4 4111〇1) were added to the solution in (1 ml). The mixture was stirred at the same temperature for 8 hours. EtO Ac was added to the reaction mixture (1 mL) and the mixture was poured into water (10 mL). The organic layer was separated, washed with water (4×5 mL), dried (Na2S04) and evaporated. The crude product was purified by preparative EtOAc (EtOAc: EtOAc: EtOAc:EtOAc: Assay data Bruton's tyrosine kinase (Btk) inhibition assay This assay captures the radioactive 33p acidified product via filtration. The interaction of biotinylated SH2 peptide receptor (Src homology) Btk with ATP results in phosphorylation of the peptide. The biotinylated product is a combined anti-streptavidin agarose bead. All bound, radiolabeled products are detected by a scintillation counter. The discs examined were 96-well polypropylene (Greiner) and 96-well 1.2 μηι hydrophilic PVDF filter plates (Millipore). The concentration reported here is the final assay concentration: 157475.doc •331· 201211039

DMSO (Burdick and Jackson) containing 10-100 μM compound, 5-10 nM Btk enzyme (His-labeled, full-length), 30 μΜ peptide receptor (Biotin-Aca-AAAEEIYGEI-NH2), 100 μΜ ATP (Sigma) , 8 mM imidazole (Sigma, pH 7.2), 8 mM 2-stone || Acid glycerol (Sigma), 200 μΜ EGTA (Roche Diagnostics), 1 mM MnCl2 (Sigma), 20 mM

MgCl2 (Sigma), 0_1 mg/ml BSA (Sigma), 2 mM DTT (Sigma), 1 33P ATP (Amersham), 20% streptavidin agarose beads (Amersham), 50 mM EDTA (Gibco), 2 Μ NaCl (Gibco), 2 M NaCl w/ 1% acid (Gibco), scintillation fluid-20 (microscint-20) (Perkin Elmer). IC5G measurements were calculated from 1 data points for each compound using data generated from a standard 96-well plate assay template. One control compound and seven unknown inhibitors were tested on each plate and each plate was tested twice. Typically, the compound is diluted in a semi-logarithmic manner starting at 1 〇〇 μΜ and ending at 3 nM. The control compound was staurosporine. The background was counted in the absence of peptide acceptor. Total activity was determined in the presence of peptide acceptors. The following protocol was used to determine Btk inhibition. 1) Sample preparation: The test compound was diluted in semi-log increments in assay buffer (imidazole, 2-glycerophosphate, EGTA, MnCl2, MgCh, BSA). 2) Bead preparation a.) rinsing the beads by centrifugation at 500 g b. Reducing the beads with PBS and EDTA to produce a 2%% bead slurry 3) No reaction at 30 ° C The mixture (assay buffer, 157475.doc • 332· 201211039 DTT, ATP, ATP) and the mixture containing the substance (assay buffer, DTT, ATP, 33PATP, peptide substrate) were pre-incubated for 15 minutes. 4) To start the assay, 10 μ]: Btk enzyme buffer (imidazole, 2-phosphoglycerol, BSA) and 10 μ] were used at room temperature: the test compound was pre-incubated for 1 〇 minutes. 5) Add 30 μί of the reaction mixture containing no substrate or substrate to the Btk and compound. 6) Incubate 50 pL total assay mixture for 3 min at 30 °C. 7) Transfer 40 μΕ of the assay solution to 150 μL of the bead sputum in the filter plate to terminate the reaction. 8) After 30 minutes, wash the filter plate as follows. 3x250 pL NaCl b. 3x250 pL NaCl containing 1% phosphoric acid c. 1x250 pL H20 9) Dry the pan at 65 ° C for 1 hour or dry at room temperature Overnight e 10) Add 50 pL of scintillation fluid-20 and count 33P cpm on a scintillation counter. Percentage of activity calculated from raw data (cpm) % activity = (sample - bkg) / (total activity - bkg) xl00 Using a single point dose response S-type model, IC50 y = A + ((BA) / (l + ((x/C)D)))) x = compound concentration, y = activity %, minutes, B = maximum value, C = IC5 〇 ' D = 1 (hill slope) measured by CD69 Inhibition of b cell activation in whole blood I57475.doc - 333 - 201211039 The procedure used to test the ability of Btk inhibitors to inhibit 3 cell receptor-mediated b cell activation in human blood is as follows: Human whole blood (HWB) is voluntary from health The person obtained 'has the following restrictions: 24 hours of banned drugs, non-smokers. The blood was collected by venipuncture to a vacuum tuber with a heparin sodium as an anticoagulant treatment. Test compounds were diluted to (7) times the desired starting drug concentration in PBS (2 〇x), followed by three-fold serial dilutions in PBS containing 1% DMSO to produce a 9-point dose response curve. Add 5·5...diluted solutions of each compound to 2 ml 96-well V chassis (Anaiytical Saies and, number 59623-23); add 5.5 μl of PBS containing 10% DMSO to control wells and no Stimulate the pores. HWB (l〇〇 μΐ) was added to each well, and after mixing, at 37 C, 5% C02 '1〇〇. /. Incubate the plate for 3 minutes at humidity. Goat F(ab')2 anti-human IgM (Southern Biotech, No. 2022-14) (10 μΐ 500 pg/ml solution, final concentration 5〇μ§/πι1) was added to each well (except for non-irritant wells) 'At the same time, mix and incubate the dish for another 2 hours. At the end of the 20-hour incubation, samples were labeled with fluorescent probes at 37t:, 5% c〇2, 100% humidity (15 μl PE mouse anti-human CD20, BD Pharmingen, No. 555623; and / or 2 〇 μ1 Apc mouse anti-human CD69, BD Pharmingen, No. 555533) incubated for 30 minutes. Induction control, unstained and single staining were included for compensation adjustment and initial voltage was not set. The sample was then dissolved in 1 ml of 1 X Pharmingen lysis buffer (bd Phamingen 'No. 555899) and the disk was centrifuged at i800 rpm for 5 minutes. The supernatant was removed via aspiration, and the remaining aggregates were again dissolved with another 1 ml of lx Pharmingen lysis buffer, and the 157475.doc - 334 - 201211039 disk was spun down as previously described. The supernatant was aspirated and the remaining aggregates were washed in FACs buffer (PBS + 1% FBS). After the final centrifugation, the supernatant was removed and the pellet was resuspended in 1800 μL FACs buffer. Samples were transferred to 96-well plates suitable for operation on an HTS 96-well system on a BD LSR II flow cytometer.

Data were obtained using the appropriate excitation and emission wavelengths of the fluorophores used and the percentage of positive cells was obtained using Cell Quest software. The initial analysis results were analyzed by FACS analysis software (Flow Jo). The concentration of CD69-positive cells that were also positive for CD20 after stimulation with anti-igM was reduced by 50% (the average of 8 control wells after subtracting the average of 8 wells of non-irritant background) was determined as a test IC50 of the compound. The IC50 value was calculated using Equation 3 using the XLfit software version 3. Representative compound data for this assay are listed in Table II below. Table II. Compound Human Whole Blood (μΜ) 1-1 0.019 1-2 0.014 1-3 0.045 1-4 0.122 1-5 0.025 1-6 0.031 1-7 0.02 1-8 0.02 1-10 0.019 1-12 0.052 1-13 0.009 1-14 0.065 1-15 0.163 1-16 0.026 1-17 0.041 1-18 0.003 1-19 0.007 1-20 0.015 157475.doc - 335 · 201211039 1-21 0.109 1-22 0.033 1-23 0.06 1-24 0.116 1-26 0.152 1-27 0.089 1-28 0.006 1-29 0.015 1-30 0.004 1-31 0.032 1-32 0.023 1-33 0.002 1-34 0.125 1-35 0.074 1-37 0.084 1 -38 0.012 1-39 0.021 1-40 0.044 1-41 0.015 1-42 0.047 1-43 0.041 1-44 0.014 1-45 0.027 1-46 0.293 1-47 0.076 1-48 0.185 1-49 0.085 1-50 0.086 1-51 0.019 1-52 0.027 1-53 0.039 1-54 0.104 1-55 0.041 1-56 0.017 1-58 0.002 1-59 0.005 1-60 0.004 1-61 0.074 1-62 0.144 1-63 0.189 1 -64 0.066 1-65 0.062 1-66 0.023 1-67 0.004 1-68 0.061 1-69 0.018 1-70 0.117 1-71 0.032

157475.doc •336- 201211039 1-72 0.056 1-73 0.03 ' 1-74 0.034 1-75 0.18 ' 1-76 0.051 1-77 0.123 1-78 0.084 — 1-79 0.06 ' 1-80 0.041 1-81 0.123 1-82 0.017 ' 1-83 0.07 ' 1-84 0.242 1-85 0.294 1-86 0.408 1-87 0.455 1-88 0.203 1-89 0.485 1-90 0.34

Inhibition of B cell activation - b cell flipr assay in Rams cells The inhibition of B cell activation by the compounds of the invention was confirmed by measuring the effect of the test compound on the anti-IgM stimulated b cell response.

The B cell FLIPR assay is a cell-based functional assay that measures the potential inhibitory effect of intracellular calcium increase caused by anti-IgM antibody stimulation. Ramss cells (Burkitt's lymphoma cell line, ATCC No. CRL-1596) were cultured in growth medium (described below). On the day before the assay, Ram〇s cells were resuspended in fresh growth medium (same as above) and placed in tissue culture flasks at a concentration of x5xl〇6/mL. On the day of the assay, the cells were counted and grown at a concentration of 1 x 丨〇6/mL in a growth medium supplemented with 1 μΜ FLUO-3 AM (TefLabs Cat. No. 0116 ' in anhydrous DMSO and 10% pluronic acid (Pluronic) Placed in acid) in tissue culture flasks and incubated for 1 hour at 370C (4% C02). To remove the extracellular dye, 157475.doc •337·201211039 cells were collected by centrifugation (5 min, 1 rpm) and resuspended in FLIPR buffer at 1 X 1 ο6 cells/ml (described below) Then, Ιχΐ05 cells/well were dispensed into a 96-well polyamin-coated black/transparent disk (BD catalog number 356692). Test compounds were added at various concentrations ranging from 100 μΜ to 0.03 μΜ (7 concentrations, detailed below) and incubated with the cells for 30 minutes at room temperature. Ramos cell Ca2+ signaling was stimulated by the addition of 10 pg/mL anti-IgM (Southern Biotech, Cat. No. 2020-01) and 96 wells were captured in FLIPR (Molecular Devices, CCD camera with argon laser at 480 nM excitation) The image of the disc is measured. Medium/buffer: Growth medium: with L-clinic acid (Invitrogen 'catalog number 61870-010), 10% fetal bovine serum (FBS, Summit Biotechnology, catalog number FP-100-05), 1 mM sodium pyruvate (Invitrogen 'catalog number 11360-070) RPMI 1640 medium. FLIPR buffer: HBSS (Invitrogen, Cat. No. 141175-079), 2 mM CaCl2 (Sigma, Cat. No. C-4901), HEPES (Invitrogen, Cat. No. 15630-080), 2.5 mM Probenecid (Sigma, Cat. No. P-8761), 0.1% BSA (Sigma, Cat. No. A-7906), 11 mM V. (Sigma, Cat. No. G-7528). Compound Dilution Details: To a maximum final assay concentration of 100 μΜ, 24 μM: 10 mM compound stock solution (prepared in DMSO) was added directly to 576 μί FLIPR buffer. The test compound was diluted in FLIPR buffer (using a Biomek 2000 robotic pipettor) to give the following dilution - 338 - 157475.doc 201211039 Protocol: vehicle, Ι.ΟΟχΙΟ·4 μ, l.ooxlO·5, 3.16 X10·6, l.OOxlO·6, 3.16X10·7, l.OOxlo.7, 3 16xl〇-8. Assays and analyses: Use the maximum-minimum statistics to report intracellular calcium increase (using the Molecular Devices FLIPR control and statistical output software, subtracted from the static baseline by the addition of stimulatory antibodies) ^ using a non-linear curve fit ( GraphPad Prism Software) Assay IC50 » Pharmaceutical compositions for the compounds of the invention for administration via several routes were prepared as described in the Examples. Composition for oral administration (A) Ingredient%, Zengqi/Jinjin active ingredient 20.0% Lactose 79.5% Magnesium stearate 0.5% These ingredients are mixed and distributed in capsules, each capsule containing about 1 〇〇 Mg ; - a capsule will be approximately equal to the total daily dose. Composition for oral administration (B) Ingredient%, weight/weight active ingredient 20.0% magnesium stearate 0.5% croscarmellose sodium 2.0% lactose 76.5% PVP (polyethylene smelting bite) 1.0% These components are combined and granulated using a solvent such as methanol. The formulation is then dried and shaped into a tablet (containing about 20 mg of active compound) in a suitable tablet machine. Composition for oral administration (C) I57475.doc -339· 201211039 Ingredient%, weight/weight active compound 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g p-hydroxybenzoate 0.15 g pair Hydroxybenzene propyl propyl ester 0.05 g Sugar granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring agent 0.035 ml Coloring agent 0.5 mg Distilled water to 100 ml These components are mixed to form Suspension for oral administration. Parenteral Formulation (D) Ingredient %, Weight/Weight Active Ingredient 0.25 g Gasified Nasate Complementary enough to make isotonic water for injection 100 ml The active ingredient is dissolved in a portion of water for injection. A sufficient amount of sodium chloride is then added with stirring to make the solution is isotonic. The solution weight was made up with the remaining water for injection, filtered through a 0.2 micron membrane filter, and packaged under sterile conditions. Suppository Formulation (E) Ingredient %, Weight/Weight Active Ingredient 1.0% Polyethylene Glycol 1000 74.5% Polyethylene Glycol 4000 24.5% These ingredients are melted together and mixed on a steam bath and poured into a containment of 2.5 g The total weight of the mold. Topical formulation (F) Ingredient _ gram 0.2-2 2 2 5 Active compound Span 60 Tween 60 Mineral oil 157475.doc -340- 201211039 Petrolatum Η) methyl p-hydroxybenzoate 0.15 propyl p-hydroxybenzoate 〇.〇 5 ΒΗΑ (butylated hydroxymethoxybenzene) 0.01 __ complement to 100_ mouse collagen-induced arthritis (mCIA) Diurnal day 'injection of collagen (id) to mice at several points on the base of the tail or on the back An emulsion in complete Freund, s adjuvant (CFA). After collagen immunotherapy, the animals will develop arthritis from about 2i to 35 days. On the 21st day, systemic administration (enhanced immunization) of collagen-containing incomplete Freund's adjuvant (Inc〇mplete Freund, s adjuvant, IFA; i.d.) was performed in synchronization with the onset of arthritis. After the 2nd day, the animals were examined daily for mild episodes of arthritis (score 1 or 2; see the description below), which is a signal to enhance immunity. After the immunization is enhanced, the mice are scored&apos; and administered with the candidate therapeutic agent over a specified time period (usually 2 to 3 weeks) and at a dosing frequency of once daily (QD) or twice daily (BID). Rat collagen-induced arthritis (rCiA) On the third day, rats were injected intradermally (i d) with emulsions of π-type bovine protein in incomplete Freund's adjuvant (IFA) at several locations on the back. On about day 7, an enhancer injection of collagen emulsion was administered at the base of the tail or at an alternative site on the back (hd.). Guanyanitis is generally observed 12 to 14 days after the initial collagen injection. From day 14 onwards, arthritis development in animals can be assessed as described below (arthritis assessment). In a prophylactic manner, the animal is given a candidate therapeutic agent at the time of the second challenge and for a specified period of time (usually 2-3 weeks) and at a frequency of once daily (QD) or twice daily (bid). medicine. 157475.doc • 341· 201211039 Arthritis Assessment: In both models, a scoring system was used to quantify the appearance of paw and limb joint inflammation. The scoring system involves evaluating 4 paws following the criteria described below: Rating: 1 = The claw or one of the toes is swollen and/or red. 2 = Two or more joints are swollen. 3 = the claw and the two or more joints involved are extensively swollen. 4 = severe arthritis of the entire claw and toe. Day 0 was assessed for baseline measurements and the assessment was started again in the first sign or swelling, up to three times a week until the end of the experiment. The arthritis index of each mouse was obtained by calculating the sum of the four scores of the individual paws to obtain a maximum score of 16 for each animal. Rat in vivo asthma model sensitized male Norwegian rat (Norway rat) with 100 Hg ΟΑ (ovalbumin) 〇 2 ml alum intraperitoneal (ip), once a week for three weeks (day 、, Brother 7 days and 14 days). Day 21 (one week after the last sensitization), 0.5 hours prior to OA aerosol challenge (1% 〇A ' for 45 minutes), vehicle or compound formulation subcutaneously once daily (qd) to rats Drug, and ends 4 hours or 24 hours after challenge. At the time of sacrifice, serum and plasma were collected from all animals for serology and pK, respectively. The tracheal cannula was inserted and the lungs were lavaged 3 times with PBS. The total white blood cell count and the classified white blood cell count of the BAL fluid were analyzed. The total number of white blood cells in the cell aliquot (20-丨〇〇 μ1) was determined by a Coulter counter. For the classification of white blood cell counts, 5 〇 2 〇〇 W samples were centrifuged in Cytospin and the slides were stained with Diff-Quik. The ratio of monocytes, eosinophils, neutrophils, and lymphocytes was counted under a light microscope using the standard 157475.doc • 342. 201211039 quasi-morphological criteria, and is expressed as a percentage. A representative Btk inhibitor showed a decrease in the total white A sphere count in the BAL of the 0A sensitized and challenged rats compared to the control amount. The foregoing invention has been described in considerable detail by way of illustration and example for the purpose of clarity and understanding. Those skilled in the art should readily appreciate that changes and modifications can be made within the scope of the appended claims. Therefore, the above description is intended to be illustrative and not restrictive. Therefore, the scope of the invention should not be determined according to the foregoing description, but should be determined in accordance with the scope of the appended claims and the full scope of the equivalents. All of the patents, patent applications, and publications cited in this application are hereby incorporated by reference in their entirety for all purposes in the the the the the .

157475.doc 343 -

Claims (1)

201211039 VII. Patent application scope: 1 · A compound of formula I, Wherein: = is a single bond or a double bond; X is CH, CH2 or N; R is Η, -R1, -RLRlR3, -W-R3 or -R2-R3; R1 is aryl, heteroaryl, bicyclic heteroaryl a base, a cycloalkyl or a heterocyclic compound, each optionally having one or more lower alkyl, hydroxy, hydroxy lower alkyl, lower alkoxy, halo, nitro, amine, lanthanide Substituent, cyano, pendant oxy (0X0) or lower haloalkyl; R2 is -C(=0), -C(=0)0, -C(=0)NR2', -NHC(=0 0, -c(R2')2, -0, -S, -C(=NH)NR2· or -S(=0)2; each R2' is independently H or lower alkyl; R3 is H Or R4; R4 is a low-blocking alkyl group, a low-carbon halogenated group, a low-carbon alkoxy group, an amine group, a lower alkylamino group, a cycloalkylamino group, a lower alkylene group, an aryl group, an aromatic group Alkyl, alkylaryl, heteroaryl, alkylheteroaryl, heteroarylalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, heterocycloalkyl, alkane 157475.doc 201211039, heterocycloalkyl, heterocycloalkyl, bicyclocycloalkyl, bicycloheterocycloalkyl, spirocycloalkyl, spiroheterocycloalkyl or bicyclospirocycloalkyl, each optionally Multiple low carbon Base, dentate, lower alkylamino, lower dialkylamino, hydroxy, hydroxy lower alkyl, lower alkoxy 'lower alkyl fluorenyl, halo, nitro, amine, hydrazine Amine, mercapto, cyano, pendant oxy, sulfonyl, lower alkylsulfonyl, fluorenyl, hydroxyamino, thiol, amine carbaryl, urethane, low dentate a carbamoyloxy, heterocycloalkyl or fluorenyl ruthenium group wherein two of the lower carbon building groups may form a ring together; Υ4 is Y4a, Y4b, Y4c or Y4d, · ¥4&amp; is 11 or halogen; Y a low &gt; 6 anti-hospital base, optionally substituted with one or more substituents selected from the group consisting of a lower carboalkyl group, a halogen, a hydroxyl group, an amine group, a cyano group and a lower alkoxy group; Y is low a carbocyclic group, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower carbon, dentate, hydroxyl, amine, cyano and lower alkoxy; Y4d is an amine group, optionally substituted by one or more lower alkyl, alkoxy lower carbon or hydroxy lower alkyl; or a pharmaceutically acceptable salt thereof. 2. As requested in the compound [the compound, where two are double bonds and χ is N. 3. The compound of claim 1, wherein two are double bonds and X is CH. 4. The compound of claim 1, wherein two are single bonds and χ is c%. 5. The compound of claim 2, wherein R*_R, _R2_R3; R1 is pyridinyl; 157475.doc 201211039 R3 is R4; and R2 is _S(=〇)2, wherein R4 is lower alkyl. 6. The compound of claim 2, wherein R is _Ri_R2_R3; R1 is a bite, R2 is -C(CH3)2; R3 is R4; and R4 is optionally substituted with one or more low carbon alkyl groups. Lower alkylamino 'lower dialkylamino or heterocycloalkyl.衣兀 7. The compound of claim 2 wherein R is _Ri-R2_R3; Ri is a stupid base. Bipyridyl; R2 is -C(= 〇); R3 is R4; and R4 is optionally substituted with or substituted with a plurality of low carbon alkyl groups. 8. The compound of claim 2, wherein Y4 is a third butyl group. 9. A compound according to claim 3 or 4, wherein γ4 is Wherein Y5 and Y6 are independently hydrazine, lower alkyl or lower haloxyalkyl. 10. The compound of claim 2, wherein γ4 is Ys Wherein Y5 is hydrazine, halogen, lower alkyl or lower haloalkyl; or Λ5*-ΝV wherein Υ5 and Υ6 are independently η or lower alkyl. I. The compound of claim 8, wherein R is _R]_R3; R1 is „ ratio. The base or the oxime is 比 ° azine; R 3 is R 4 ; and R 4 is an optionally substituted lower alkyl group. And a heterocyclic alkyl or a pyridyl group. 157475.doc 201211039 12. The compound of claim 8, wherein the ruler is _ri_r2_r3; Ri is pyridyl; R is -C(CH3)2; R3 is R4; And R4 is a lower alkylamino group, a lower dialkylamino group or a heterocycloalkyl group optionally substituted with one or more lower carbon groups. 13. The compound of claim 8, wherein R is _r _r2_r3; Ri is pyridyl; R2 is -C(=0); R3 is R4; and R4 is optionally substituted heterocycloalkyl or bicyclospirocycloalkyl. 14. The compound of claim 13, Wherein R4 is a substituted or otherwise sputum. 15. The compound of claim 1 which is selected from the group consisting of: 6-t-butyl-2-(3-{5-[5- (1-ethylamino-1-methyl-ethyl ratio. 1,4--2-aminoamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl }_2-hydroxyindole-stupyl)_8_fluoxazine-1-one; 6-t-butyl-8-fluoro-2-(2-hydroxyindenyl-3-{l-fluorenyl-5- [5-(morpholin-4-number) _°bipyridin-2-ylamino]-6-sideoxy-1,6-dihydro-pyridazine-3-yl h-phenylpyridazine-butanone; 6·t-butyl-8- Fluorin-2_{2-hydroxyindolyl-3-[5-(5-.methanesulfonyl-0-11-denyl-2-ylamino)___mercapto_6_sideoxy_丨,6 _Dihydro-pyridazine-3-yl]-phenyl b 2 oxazin-1-one; 6_t-butyl-8-fluoro-2-(2-hydroxydecyl-3-{5-[ 5-(3-decyloxy-azetidin-1-ylindenyl)-pyridin-2-ylamino]-1-indolyl-6-yloxy-1,6-dihydro-indole Pyridazin-3-yl}-phenyl)-2//-pyridazin-1-one; 6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3-{l-methyl- 5-[5-(8-Methyl-3,8-diaza-bicyclo[3.2.1]oct-3-ylindenyl)-pyridin-2-ylamino] I57475.doc -4- 201211039 Side Oxy-1,6-diaza-adazol-3-yl}•phenyl)-2 σσ--1 -嗣; 6-second butyl-2-(3-{5-[5-( 2-didecylamino-1,1·didecyl-ethoxy)~° ratio. 1,4-ylamino]-1-indolyl-6-sideoxy-1,6-diaza -Dalazine-3-ocyl}-2-hydroxymethyl-phenyl)-8-fluoro-2^-pyridazin-1-one; 2-{3-[5-(5-gas-mixed diced-- 1-ylmethyl-° ratio of dec-2-ylamino)-1 -methyl-6-oxirane-1,6-·one-shenry-3-yl ]-2-methyl-phenyl}-6-t-butyl-8-fluoro-2/ί-pyridazin-1-one; 6-dibutyl-2-(3-[5-( 5. Dimethylaminomethyl ° ratio. Des-2-ylamino)-1-indolyl-6-o-oxy-1,6-diaza-d. Qin-3-yl]-2-methyl-styl}-8-gas-2Η-bleaching-Qin-1-Gu 1,6-Tertibutyl-2-(3-{5-[(lR , 5S)-5-(3,8-diaza-bicyclo[3·2·1]oct-8-ylpyridin-2-ylamino]_1-fluorenyl-6-oxirane-1, 6-diaza-enoxa-3-yl}-2-fluorenyl-phenyl)-8-gas-2Η·^.-1-嗣; 6-{6-[3-(6-second -8-8-gas-1-sideoxy-111-.t-Chinter-2-yl)-2_ fluorenyl-phenyl]-2-mercapto-3-yloxy-2,3-dihydro - 嗓-4-ylaminodipurin, Ν-dimercapto-nicotinium amide; 6-second butyl-8-gas-2-{2-罗生曱基-3-[1-曱Keto-6-sideoxy-5_(5-dimethylmethyl-σ-pyridin-2-ylamino)-1,6-diaza-chiral-3-yl]-phenyl}_ 2^1 - blowing ° Qin-1-one; 6-t-butyl-8-lact-2-(3-{5-[5-(2-propionyl-1,1-dimethyl-ethoxy)- °°°-2-ylamino]-1-methyl-6-sideoxy-1,6-di-gas-healing-Qin-3_yl}-2_methyl-phenyl)-2 / /-Blowing -1 -嗣, 2-(3-{5·[5-(2-azetidin-1-yl-1,1-didecyl-ethoxy)-pyridyl. 2-aminoamino]-1 -mercapto-6-o-oxy-1,6-diaza-dama-3-yl} - 2 -light I57475.doc 201211039 fluorenyl-phenyl)-6- three -8-8-gas-° too 0 Qin-1 -嗣; 6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3-{5-[5-(2-hydroxy-2-) Mercapto-propoxy)-pyridin-2-ylamino]-1-indolyl-6-o-oxy-1,6-dihydro-pyridazin-3-yl}-phenyl)-2 /7-oxazin-1-one; 2-[8-fluoro-2-(2-hydroxymethyl-3-{l-methyl-5.[5-(morpholin-4-carbonyl)-pylo] Di-2-ylamino]-6-o-oxy-1,6-diaza-violet^-yl}-phenyl)-1-yloxy-1,2-dihydro-isoquinoline- 6-yl]-2-mercapto-propionitrile; 6-t-butyl-8-fluoro-2-(3-{5-[5-((S)-2-hydroxy-3-decyloxy-) Propoxy)_11 is more than benzyl-2-ylamino]-1-indolyl-6-yloxy-1,6-diaza-contained-3-yl}-2-hydroxymethyl-phenyl)- 2//-pyridazin-1-one; 6-t-butyl-8-fluoro-2-(3-{5-[5-((R)-2-hydroxy-3-methoxy-propoxy) ))-D ratio -2-ylamino]-1-methyl-6- oxo-1,6-diaza-indolyl-β-methyl}-2-hydroxymethyl-phenyl)- 2/Λ· pyrazin-1-one; 6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3_{1-mercapto-5-[5-((S)-l- Methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-6-hydroxyl-1,6-dihydro-pyridazin-3-yl}-styl)-2 ugly-pyridazine 1-ketone; 6-t-butyl_8_fluoro-2-(2-hydroxymethyl-3- {l-Methyl-5-[5-((R)-l-indolyl-pyrrolidin-2-yl)·pyridin-2-ylamino]-6-sideoxy-1,6- Dihydro-pyridazin-3-yl}-phenyl)-2 ugly-pyridazin-1-one; 6-{6-[3-(6-t-butyl-8-fluoro-1-yloxy) -1//-pyridazin-2-yl)-2-hydroxydecyl-phenyl]-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino} -#,#-dimercapto-nicotine decylamine; 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-4-methyl) Benzyl-piperidine-1-carbonyl)-pyridin-2-ylamino]-1-methyl-6-yloxy-1,6-dihydro-157475.doc 201211039 pyridazin-3-yl}-benzene 2)-/-pyridazin-1-one; 6_t-butyl-8-fluoro-2-(2-pyridyl-3-{l-methyl-5-[5-(6- Mercapto-2,6-diaza-spiro[3·3]heptan-2-yl)-pyridin-2-ylamino]_6_sideoxy-1,6-mono-p-azine-3-yl }-Phenyl)-2//-Blowing 嗓 ι ketone; 6-Tertibutyl-2_{3-[5-(5-ethanesulfonyl-pyridyl-2-ylamino)-i - mercapto-6-o-oxy-1,6-dihydro-pyridazin-3-yl [mu]-hydroxymethyl-phenyl b-8-fluoro-2/f-pyrazin-1-one; 6-third Butyl-8-fluoro-2-(2-hydroxyindolyl-3-{l-methyl-6-oxo-5-[5-(propane-2-sulfonyl)-pyridine-2-yl) Aminodibuquinone dihydro-pyridazine_3- }-phenyl phenyl oxazinone; 6-second butyl-8-fluoro 2 -(3-{5_[5-(2-hydroxy-ethylthio)_&lt;»bipyridin-2-ylamine Base]-1-indenyl_6_sideoxy q,. Dihydro-pyridazine·3_yl}_2-hydroxyindole-benyl)-2//-°-azinone; 6-t-butyl-8-fluoro-2·(3·{5_[5_( 2-hydroxy-ethanesulfonyl)- 0-pyridyl-2-ylamino]_1_mercapto-6-sidedoxy-1,6-dihydro-pyridazin-3-yl}-2-hydroxy Methyl·phenyl)_2-pyridazine heart-ketone; 6_t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-isopropyl)- Piperazine_1-yl)-pyridin-2-ylamino]·^methyl_6_sideoxy-丨,6-dihydro-pyridazine_3_yl}-phenyl)-2-pyridazine _丨_ketone; 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{l-fluorenyl-5-[5-(l-methyl-) 疋3-yl )-η ratio dimethylamino]_6_sideoxy-1,6-dihydro-»da--3-ylbuphenyl)_2-pyridazine-i-one; 6_second butyl' 8-fluoro-2-{2-hydroxyindolyl-3-[5-(1,-isopropyl- Γ'2',3',4',5',6'-hexahydro-[3,4 ']bipyridyl-6-ylamino)-1-indolyl-6-side 157475.doc 201211039 Oxy-1,6-diox-violy-qin-3-yl]-phenyl}-2 blowing. Qin-1 -嗣, 6-t-butyl-2-{3-[5-(1'-ethylhexahydro-[3,4']-linked.pyridin-6-ylamino)-1- Indole-6-sideoxy-1,6-dihydro-pyridazin-3-yl]-2-fluorenyl-phenyl} - 8 - said -2 //- °大嘻-1 -嗣, 6-Tertibutyl-2-{3-[5-(l,5-dimethyl-1//-pyrazol-3-ylamino)-1-indolyl-6-sideoxy-1 ,6-dihydro-pyridazin-3-yl]-2-hydroxydecyl-phenyl}-8-gas-2 good-blowing °Q-1·ketone; 6-t-butyl-8-dun- 2-(2- mercapto-3-{l-fluorenyl-5-[5-((S)-l- fluorenyl-.bilo-dec-3-yl)-° ratio °-2 Amino]-6-tertiaryoxy-1,6-di-rho--. Qin. 3-yl}-phenyl)-2--. Taiqi Qin-1 - 酉, 6-t-butyl-8-gas-2-(2-methyl-3-{1-indolyl-5-[5-((R)-1 _ 曱--σ 比洛. 定-3 -yl)-. Ratio. -2 -ylamino]-6-o-oxy-1,6-diaza-pyridazin-3-yl}-phenyl)- 2//-pyridazin-1-one; 6-t-butyl-8-l-2-{2-pyridyl-3-[1-indolyl-5-(4-methyl- 3,4 ,5,6-tetrahydro-2i/-[l,2']bipyrazin-5'-ylamino)-6-o-oxy-1,6-diaza-daind-3-ylbenzene }} - 2 π太嗓-1 - 酉, 6-t-butyl-2-{3-[5-(5-cyclobutylaminomethyl-pyridazin-2-ylamino)-1 -Methyl-6-o-oxy-1,6-diaza-dain-3-yl]-2-methyl-phenyl}-8-gas-27/-. Large ° Qin-1 - repaid, 6-t-butyl-2-(3-{5-[5-(2-didecylamino-ethoxy)-° than 嗓-2_ylamino]- 1-methyl-6-tertiaryoxy-1,6-diox-.1717-methyl-3-yl}-2_methyl-phenyl)-8-fluoro-2/f-pyridazine-1 -ketone; 6-t-butyl-8-espan-2-(2-methyl-3-{l-methyl- 5-[5-(4-indolyl)-D-inden-1-yl Base) _° 比-2-ylamino]-6-sideoxy-1,6-diaza- ol 157475.doc 201211039 azine-3-yl}-phenyl)-27/-pyridazine-1 -ketone; 6-t-butyl-2-(3-{5-[5-(2-didecylamino-1,1-didecyl-ethoxy)-. Amino]-1-indolyl-6-o-oxy-1,6-diaza- olfactory-3_yl}-2-hydroxyindolyl-phenyl)-8-fluoro-2//-pyridazine 1-ketone; 6-t-butyl-2-(3-{5-[6-(2-dimethylamino-1,1-dimethyl-ethoxy)-jian 11 Qin-3 -ylamino]-1-methyl-6-o-oxy-1,6-dihydro-anthracene-3-yl]'-2- mercapto-phenyl)-8-gas-2/ϊΓ - blowing α Qin-1 -顚I, 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-indolyl-5-[6-(1-indolyl-branches咬-4-yl)- 嗓-3-ylaminoamino]-6-sideoxy-1,6-diaza-11 达-3-yl} •phenyl)-2//- blowing ° Qin -1 - Display I, 6- Tributyl-8-fluoro-2-(2-hydroxymethyl-3-{1-indolyl-5-[5-(4-methyl-0-indolyl)-yl)-. Ding-2-ylamino]-6-o-oxy-1,6-diaza-pyridazin-3-ylpyryl)-2//-pyridazin-1-one; 6-t-butyl -8-fluoro-2-[2-hydroxyindolyl-3-(5-{5-[(2-decyloxy-ethylamino)-indolyl]-pyridin-2-ylamino}-1 -methyl-6-o-oxy-1,6-dihydro-pyridazin-3-yl)-phenyl]-2 ugly-pyridazin-1-one; 6-t-butyl-8-fluoro- 2-(2-hydroxyindolyl-3-{1-methyl-5-[5-((lS,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]heptane- 2-ylmethyl)-pyridin-2-ylamino]-6-tertiaryoxy-1,6-diaza-indol-3-yl}-phenyl)_2 //π太嘻-1 _ ketone 6-Tertibutyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-{[(2-decyloxy-ethyl)-indolyl-amino]-anthracene }}-° ratio. -2--2-ylamino)-1-indolyl-6-sideoxy-1,6-di-rat-°°qin-3-yl]-phenyl}-2if-° Taichung-1 - 酉, 6-t-butyl-8-fluoro-2-(2-hydroxyindolyl-3-{1-methyl-5-[6-(4-methyl- 157475. Doc 201211039 ° bottom 嗓-1-base)-嗔. Qin, 3_ylamino]_6_sideoxy_i,6-dihydro-pyridazine-3-yl}-phenylpyridazine ketone; 6_t-butyl-8-fluoro-2-( 2-Hydroxymethyl-3-{l-fluorenyl-5-[6-((lS,4S)-5-mercapto-2,5-dioxa-bicyclo[2.2.1]heptan-2-yl )-pyridazin-3-ylamino]-6-oxy-1,6-dihydro-pyridazine-3-yl}-phenyl)·2-pyridazinone; (($[5~( Azacyclobutane-1 _ _ carbyl) _. 咬-2_ylamino]-1 -methyl-6- oxirane-1,6-dihydro-pyridazine _3 丨 _2 _hydroxymethyl_phenyl)_6_yl 8_fluoro-2/f_D-Terazine ketone; 6-th:r butyl-]violet-2-(3-{5_[5-(i,1- Bilateral oxy-U6-thiomorpholin-4-yl-yl)-. 比0, _, glycyl, ylamino]-1-indolyl-6-sideoxy-1,6-diaza-嘻-3- Earth} 2 hydroxymethyl-phenyl)-8-fluoro-2i/-pyridazin-1-one; 6-第= _ dibutylfluoro-2-(2-hydroxymethyl-3 -{l-methyl-5-[5-(2-oxa-6aza-spiro η·]heptan-6-yl)-° ratio -2-2-amino group]-6-side Oxy-gas-trim-3-ylbupropyridazin-1-one; 6~ r: 0, dibutyl_8_fluoro-2-(2-hydroxymethyl-3-{l- Methyl-5-[5-(6-methyl-diazoidene '' snail [3.3] heptane-2 -yl)-indole ratio 0--2-amine ]]-6-side oxo-oxo-pyridazin-3-yl}-phenyl)-2//-pyridazin-1-one; ^'{6&gt;f3 ft- ^ -(6•t-butyl -8-fluoro-1-oxo-l/ί-pyridazin-2-yl)-2-carboxylidene-sodium-benzyl]-2-mercapto-3-yloxy-2,3- Dihydro-pyridazin-4-ylamino} 'dimethylamino-ethyl)-nicotinium amide; 6'{6^f3 ((·^ tert-butyl-8-fluoro-1- side Oxy-1 ugly-pyridazin-2-yl)-2-transformed ~ soil, benzyl]-2-mercapto-3-yloxy-2,3-dihydro-pyridazin-4-yl Amino}) g-ethyl-ethyl)-iv-methyl-nicotinium amide; r_ 1 [3-(6_t-butyl-8-fluoro-1-yloxy-l/f-pyridazine -2-yl), 157475.doc 201211039 2-Hydroxymethyl-phenyl]-2-mercapto-3-yloxy-2,3-dihydro-pyridazin-4-ylamino}-pyridine- 3-carbonyl)-azetidin-3-indene nitrile; 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(3-hydroxy-pyrrole) Acridine-1-yl)-° ratio nitr-2-ylamino]-1-methyl-6-o-oxy-1,6-dihydro-indole-methyl-3-yl}-phenyl)- 2//-pyridazin-1-one; 6-t-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[5-(4-hydroxy-piperidin-1-number) Base)-° ratio sigma-2-ylamino]-1-indolyl-6-sideoxy-l,6-di-argon- Qin ° --3-yl} - phenyl) -2 // - phthalazine-1-one; 6-tert-butyl-8-fluoro-2-(2-hydroxyf-yl-3-{1-indolyl-5-[5-(4-methyl-0-[beta]-l-yl)-° °定-2-ylamino]-6-sideoxy-i,6-diamino- benzyl-3-yl}-phenyl)-2//-pyridazin-1-one; 6- Tributyl-2-(3-{5-[5-((S)-l,2-di-yl-ethyl)-°°°qin-2-ylamino]-1-methyl-6 - sideoxy-1,6-dihydro-pyridazin-3-yl}-2-hydroxyindolyl-phenyl)-8-fluoro-2//- °Taiqin-1 -嗣; 2-{ 3-[5-(5-aza- butyl ketone-1-ylindenyl-1-methyl-1 oxime. Sodium-3-aminocarbyl)-1-methyl-6-sideoxy- 1,6-dihydro-pyridazin-3-yl]-2-hydroxyindolyl-phenyl}-6-tert-butyl-8-fluoro-2/-pyridazin-1-one; 6- Tributyl-8-fluoro-2-{2-hydroxyindolyl-3-[1·indolyl-5-(5-mercapto-4,5,6,7-tetrahydro-pyrazolo[1, 5_α]pyrazin-2-ylamino)-6-o-oxy-1,6-dihydro-d-Chent-3-yl]-phenylisoazin-1-one; 6·t-butyl- S-fluoro-2-{2-hydroxyindenyl. -[imethyl_5_(5_oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolopyrazine memantamine) pendant oxy-1,6-dihydro-indole Pyrazin-3-yl]-phenylindole_丨--6-t-butyl-8-fluoro-2-{3-[5-(1,,2Ά4,,5,,6,α- 'HU ,] 157475.doc -11- 201211039 ° ratio of α--6-ylamino)-1 -methyl·6-sideoxy-1,6-dipho-11-indol-3-yl]-2 -hydroxyindole-phenylpyridazin-1-one; 6-t-butyl-8-fluoro-2-{2-hydroxyindol-3-[5-(1'-nonanesulfonyl-1 |,2|,3|,4|,5|,6'-hexahydro-[3,4*]-bipyridin-6-ylamino)-1-indolyl-6-sideoxy-1 ,6-diaza-slit °Qin-3 -yl]•phenyl} - 2 ° too D Qin-1 -嗣, 2-{3-[5-(1'-ethylidene-re'J,〆 '.1',-Hexahydro-[3,41]biacridin-6-ylamino)-1 -methyl-6-tertiaryoxy-1,6-distributor-d-Qin-3-yl ]-2 - fluorenyl phenyl}-6-second butyl-8- defeat-2//•Blowing 嘻-1 -S, 6-t-butyl-8-fluoro-2-{2 -hydroxyindole~3-[5-(4-hydroxy-4-indolyl-3,4,5,6-tetrahydro-27/-[1,3']bipyridin-6'-ylamino) -1-methyl-6-sideoxy-1,6-di-rhamn-slit σ-qin-3-yl]-phenyl} - 2 //-blow-1 - 酉6-t-butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(4-hydroxy-3,4,5,6-tetra--2--[ 1,31 ]联.Bite -6 '-ylamino)-1 -methyl-6-sideoxy-1,6-two wind-*5^. Qin-3-yl]-benton} - 2 //- blowing D Qin-1 -嗣, 6-second butyl-8-gas-2-(2-methyl-3-{l-fluorenyl) -5-[5_((lR,5S)-3-indolyl-3,8-diaza-bicyclo[3.2_1]oct-8-yl:l·pyridin-2-ylamino]-6-side Oxy-1,6-dimole-°-indolyl-3-yl}-phenyl)-2 σ-t-butan-1-one; 6-t-butyl-8-fluoro-2-{2-hydroxyindole Benzyl-3-[1-indolyl-5-(1'-fluorenyl-hexahydro-[3,4']-linked.pyridin-6-ylamino)-6-sideoxy-1,6- Diazo-chino-Qin-3-yl]-phenyl}-2 //-Blowing 嗓-1 -嗣, 6-Tert-butyl-2-(3-{5-[l-((R)-- 2,3-dihydroxy-propyl)-1//-pyridinyl-ylidene-3-ylamino]-1 -f-yl-6-o-oxy-1,6-diaza-chitrile基}-2 - 曱基-笨基)-8 -气-2 //-Blowing 嗓-1 - 酉, 157475.doc -12- 201211039 6-Third Butyl-2-(3-{5_ [5_(4_Ethyl-piperazinepyridin-2-ylamino)-1-methyl-6-yloxy-oxime, dihydro-pyridazine_3_yl}_2-hydroxyindoleyl_phenyl )-8-fluoro-2 good-blowing 嘻-1; 6-third yl-8-fluoro-2-(2-hydroxyindenyl.-7屮*hydroxy-2-methyl-propyl)-1/ /-pyrazol-3-ylamino]]"methyl_6_sideoxy-丨,6-dihydro-pyridazin-3-yl}-phenyl)-2//-pyridazine_丨_ ketone; 2_(8_ fluoro_2_{2_ hydroxydecyl-3-[l-fluorenyl_5-(1,-methyl- l·, 2l,3',4',5|,6|-hexahydro-|| ;3,4l]linked tI than pyridine-6 amino group) ό 侧 侧 _ _ 1 '6-dihydro-indol-3-yl μ stylyl}] _ side oxydihydro-iso- 啥 _ 6-yl)-2-methyl-propionitrile; 2-(2-{3-[5-(5-azetidin-1-ylindenyl-1-methyl·1沁pyrrole_ 3- Aminomethyl)-1-methyl-6-sideoxy.π-dihydro-conazole _3_yl]·2_methyl-phenyl}-8-fluoro-1-oxo-oxime, Dihydro-isoquinoline-6-yl)_2-methyl-propionitrile; 2-[2-(3-{5-[5-(2-azetidinyl)i___曱-Ethyloxy)-pyridin-2-ylamino group μκ曱yl_6_sideoxy-丨,6•dihydro-pyridazine_3_yl}-2-hydroxymethyl-phenyl)-8- Fluor-1-oneoxyd, d-dihydro-isoquinoline-6-yl]-2-mercapto-propionitrile; 2-(8-fluoro-2-{2-hydroxymethylmethyl_5_( 5_methyl_4,5,6,7 tetrahydrogen 〇 并 and [1,5-α]pyridazine-2-aminol)_6_side oxime,6·dihydroxazine-3- ]]-phenyl}-1. oxo-1,2-dihydro-isoquinoline-6-yl)_2-fluorenyl-propanenitrile; 6-(6·{3-[6-(cyano) -dimethyl-indenyl)_8_fluoro-b-oxyl^open-isoquinolin-2-yl]-2- Hydroxymethyl-phenyl}_2-methyl-3-oxo-2,3-dihydro-157475.doc •13· 201211039 pyridazin-4-ylamino)-#,#-didecyl- Nicotine amide; 2-[8-fluoro-2-(2-methyl-3-{l-fluorenyl- 5-[5-((S)-l-methyl-0) -2-base)-. ratio. -2 -aminoamino]-6-tertiaryoxy-1,6-di-s-nonyl-3-yl}-phenyl)-1-yloxy-1,2-dihydro-isoquinoline -6-yl]-2-mercapto-propionitrile; 2-[8-fluoro-2-(2-hydroxymethyl-3-{l-methyl-5-[5-((S)-l-) Methyl-pyrrole-3-yl)-11-biti-2-ylamino]-6-o-oxy-1,6-dihydro-indol-3-yl}-phenyl)-1- side Oxy-1,2-dihydro-isoquinolin-6-yl]-2-indolyl-propanenitrile; 2-[2-(3-{5-[5-(2-azetidine-) 1-yl-1,1-dimethyl-ethoxy)-.Bis-2-ylamino]-1-indolyl-6-oxirane-1,6-diaza-嗔° Qin- 3-yl]^-2-pyridyl-phenyl)·8-gas-1-o-oxy-1,2,3,4-tetrazine-isoindol-6-yl]-2-methyl -propionitrile; 2-(8-fluoro-2-{2-hydroxymethyl-3-[l-fluorenyl-5-(5-oxetan-3-yl-4,5,6,7 -tetrahydropyrazolo[1,5-α]pyrazin-2-ylamino)-6-o-oxy-1,6-dihydro-pyridazin-3-yl]-phenyl}-l- Sideoxy-1,2-dihydro-isoquinolin-6-yl)-2-mercapto-propanenitrile; 6-t-butyl-8-fluoro-2-{2-hydroxyindolyl-3- [l-Methyl-5-(1·-oxetan-3-yl-l',2',3',4,5',6--hexahydro-[3,4'] Than 6-ylamino)-6-o-oxy-1,6-dihydro-pyridazin-3-yl]-phenyl} -2/ί-pyridazin-1-one; 2-(8-fluoro-2-{2-hydroxymethyl-3-[1_methyl-5-(oxime-oxetan-3-yl) -1,,2,,3',4',5',6'-hexahydro-[3,4,]bipyridylsylamino)-6-o-oxy-1,6-dihydro-da °Qin-3-yl]-styl}_1_sideoxy-1,2-dihydro-iso-O||leaved-6-yl)-2-methyl-propionitrile; 6_t-butyl- 2_{3-[5-(5-ethyl·4,5,6,7-tetrahydro-pyrazolo[I,5-α]0hept-2-ylamino)-1 -methyl_ 6-Sideoxy-1,6-dihydro-vioron-3-yl]- 157475.doc -14- 201211039 2-methyl-phenyl}-8-gas-2//·σ嘻- 1-class; 2-(2-{3·[5-(5-ethyl-4,5,6,7-tetrahydro-oxazolo[1,5·α].pyrazine·2·ylamine 1-methyl-6-o-oxy-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl-b-fluoro-1-oxo-oxyl-1, 2-dihydro-isoquinolin-6-yl)-2-mercapto-propanenitrile; 6-t-butyl-2-[3-(5-{5-[(lS,4S)-l-( 2,5-diaza-bicyclo[2.2.1]hept-2-yl)methyl]-pyridin-2-ylamino}-1-methyl-6-o-oxy-1,6-di Hydrogen-pyridazin-3-yl)-2-hydroxyindolyl-phenyl]-8-fluoro-2//-pyridazine-1-one; 6-t-butyl-8-fluoro-2-(2) -Hydroxymethyl_3-{5-[5-(4-hydroxy-4-methyl-pie. -1 -ylmethyl)-° ratio bit-2-ylamino]-1 -methyl-6-tertiaryoxy-1,6-diaza-triazin-3-yl}-phenyl)- 2 blowing ° Qin-1 -嗣, 4·(6-{6-[3-(6-苐dibutyl-8-accord-1-yloxy-1 σσ秦_2-yl)_ 2- Methyl-phenyl]-2-mercapto-3-yloxy-2,3-dihydro-. ° 秦 -4- ylamino}}pyridin-3-yl)-piperazine-1- Ethyl formate; 8- gas-6-(2-a-1,1-didecyl-ethyl)-2-(2-sulfanyl-3-{1-mercapto-5-[5-( 】 吗 -4 - ) ) - - - - ) ) ) -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -isoindol-1 -嗣; 6-t-butyl-8-fluoro-2-(2-hydroxyindole-3-{1-methyl-5-[5-((lS,4S)-5) -methyl-2,5-diaza-bicyclo[2.2.1]heptan-2-yl)-pyrazin-2-ylamino]-6-o-oxy-1,6-di-rhen -3-ylphenyl)-2 blowing σ Qin-1 -S, 2-[8-fluoro-2-(2-hydroxyindenyl-3-{1-indolyl-5-[5_((R)) -L· 曱 比 比 σ -3- -3- -3- 基 基 基 基 基 定 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -1-flank-1,2-dimur-isoindole _6_yl]-2-methyl-propy; and 157475.doc -15- 201211039 6-Third butyl_8-fluoro-2-(2-hydroxyindolyl-3-{l-fluorenyl-6-yloxy-5-[Γ-(2,2,2-trifluoro-) Ethyl)_11,2,3,4,5,6,6-hexahydro-[3,4,]bipyridyl-6-ylamino]-1,6-dihydro-pyridazine-3 -yl}-phenyl)-2indole-pyridazin-1-one. The use of a compound according to any one of claims 1 to 15 which is for the manufacture of a medicament for the treatment of an inflammatory condition and/or an autoimmune condition. 17. Use of a compound according to any one of claims 1 to 15 for the manufacture of a medicament for the treatment of rheumatoid arthritis. 18. Use of a compound according to any one of claims 1 to 15 for the manufacture of a medicament for the treatment of asthma. A pharmaceutical composition comprising a Btk inhibitor compound according to claim 1 in admixture with at least one pharmaceutically acceptable carrier, excipient or diluent. 0. Claims 1 to 8 and 10 A compound according to any one of the preceding claims, which is for use as a therapeutically active substance. The compound of any one of claims 1 to 8 and 10 to 15 for use in the treatment of an inflammatory condition and/or an autoimmune condition. 157475.doc 201211039 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 157475.doc