HK1203934B

HK1203934B - Pyridazine amide compounds and their use as syk inhibitors

Info

Publication number: HK1203934B
Application number: HK15104335.9A
Authority: HK
Inventors: Johannes Cornelius Hermann; Joshua Kennedy-Smith; Matthew C. Lucas; Fernando Padilla; Michael Soth
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2012-01-10
Filing date: 2013-01-07
Publication date: 2017-12-15

Description

Pyridazine amide compounds and their use as SYK inhibitors

Protein kinases constitute one of the largest families of human enzymes and regulate a variety of different signal transduction processes by adding phosphate groups to proteins; in particular tyrosine kinases phosphorylate the alcohol moiety of tyrosine residues of proteins. The tyrosine kinase family includes members that control cell growth, migration, and differentiation. Abnormal kinase activity is implicated in a variety of human diseases, including cancer, autoimmune and inflammatory diseases. Since protein kinases are important regulators of cell signal transduction, they provide a means to modulate cellular function using small molecule inhibitors of kinase activity and are therefore good targets for drug design. In addition to treating kinase-mediated disease processes, selective and potent inhibitors of kinase activity may also be useful in studying cellular signal transduction processes and in identifying other therapeutically beneficial cellular targets.

SYK (spleen tyrosine kinase) is a non-receptor tyrosine kinase that is required for B cell activation through BCR signaling. SYK is activated upon binding to phosphorylated BCR, initiating early signaling events following BCR activation. SYK deficient mice display an early block of B cell development. Therefore, inhibition of SYK enzymatic activity in cells by its effect on autoantibody production is proposed as a treatment for autoimmune diseases.

In addition to roles in BCR signaling and B cell activation, SYK also plays an important role in FcRI-mediated mast cell degranulation and eosinophil activation. Thus, SYK is implicated in allergic disorders including asthma. SYK binds via its SH2 domain to the phosphorylated γ chain of Fc γ RI and is essential for downstream signaling. SYK deficient mast cells indicate defective degranulation, arachidonic acid and cytokine secretion. This is also shown for pharmacologically active agents that inhibit SYK activity in mast cells. Treatment with SYK antisense oligonucleotides inhibited antigen-induced infiltration of eosinophils and neutrophils in an asthma animal model. SYK-deficient eosinophils also display a dysactivation of the FcR stimulatory response. Thus, SYK small molecule inhibitors may be useful in the treatment of allergy-induced inflammatory diseases including asthma.

In view of the numerous conditions covered which may benefit by treatment involving modulation of the SYK pathway, it is apparent that novel compounds which modulate the SYK pathway and methods of using these compounds should be capable of providing substantial therapeutic benefit to a wide variety of patients. The present application provides novel compounds for the therapeutic treatment of autoimmune and inflammatory diseases by targeting the SYK pathway or by inhibiting SYK kinase.

The application provides compounds of formula I

Wherein:

a is cycloalkyl or heterocycloalkyl;

each X is independently amino, C (═ O) NHR, C (═ O) R, C (═ O) OR, NHC (═ O) R, CH₂NHR, lower alkyl, hydroxy lower alkyl or hydroxy lower alkylamino;

each R is independently H or R';

each R' is independently lower alkyl, heterocycloalkyl, phenyl, heteroaryl lower alkyl, or bicyclic heteroaryl, optionally substituted with one or more R ";

each R "is independently hydroxy, lower alkylamido, carboxy, oxo, lower alkoxy, lower alkylamino or lower dialkylamino;

m is 0, 1 or 2;

b is phenyl or a monocyclic or bicyclic heteroaryl;

each Y is independently halogen, lower alkyl, lower alkoxy, lower haloalkyl, lower hydroxyalkyl, heteroaryl, lower alkylsulfonyl, cycloalkyl, heteroaryl, or heterocycloalkyl; and is

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

The present application provides a method of treating an inflammatory or autoimmune disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.

The present application provides pharmaceutical compositions comprising a compound of formula I admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

Definition of

The phrase "a" or "an" entity as used herein refers to one or more of the entity; for example, a compound refers to one or more compounds or at least one compound. Thus, the terms "a" (or "an"), "one or more" and "at least one" are used interchangeably herein.

The phrase "as defined above" refers to the broadest definition of each group provided in the summary of the invention or the broadest claims. In all other embodiments provided below, substituents present in each embodiment and not explicitly defined retain the broadest definition provided in the summary of the invention.

As used in this specification, the terms "comprises" and "comprising," whether in transitional phrases or in the body of a claim, should be construed to have an open-ended meaning. That is, the term should be construed as synonymous with the phrase "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the recited steps, but may include additional steps. The term "comprising" when used in the context of a compound or composition means that the compound or composition includes at least the recited features or components, but may include other features or components.

As used herein, the word "or" is used in the "inclusive" sense of "and/or" and not the "exclusive" sense of "either/or," unless explicitly stated otherwise.

The term "independently" as used herein means that the variables can apply to either case regardless of the presence or absence of the variable within the same compound having the same or different definition. Thus, in a compound where R "occurs twice and is defined as" independently carbon or nitrogen, "both R" can be nitrogen or one R "can be carbon and the other nitrogen.

When any variable occurs more than one time in any moiety or formula depicting and describing compounds used or claimed in the present invention, its definition at each occurrence is independent of its definition at other occurrences. Moreover, combinations of substituents and/or variables are permissible only if the compound is a stable compound.

The symbol "+" at the end of a bond or "- - - -" through a bond each refers to the point of attachment of a functional group or other chemical moiety to the rest of the molecule of which it is a part. Thus, for example:

MeC(＝O)OR⁴whereinOr

A bond drawn to a ring system (as opposed to being attached to a different vertex) means that the bond can be attached to any suitable ring atom.

As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted" means that the optionally substituted moiety may incorporate a hydrogen atom or substituent.

The phrase "optional bond" means that the bond may or may not be present, and that the specification includes single, double or triple bonds. If a substituent is designated as "bond" or "absent," the atoms attached to the substituent are directly attached.

The term "about" as used herein means about, near, about or about. When the term "about" is used in combination with a numerical range, it modifies that range by derivatizing the upper and lower boundaries of the numerical range. Generally, the term "about" is used herein to modify a numerical value by 20% above or below the stated value.

Some compounds may exhibit tautomerism. Tautomeric compounds can exist as two or more species that can interconvert. Prototropic tautomers are caused by the migration of covalently bonded hydrogen between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers generally result in a mixture whose chemical and physical properties are consistent with a mixture of multiple compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketoform predominates; whereas in phenols the enol form predominates. Common prototropic tautomers include keto/enolAmide/imide acidsAnd amidinesTautomers. The latter two are particularly common in heteroaryl and heterocyclic rings, and the present invention encompasses all tautomeric forms of these compounds.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The present application refers to a variety of methodologies and materials known to those skilled in the art. Standard reference tools describing general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of therapeutics,10^thEd., McGraw Hill Companies Inc., New York (2001). Any suitable materials and/or methods known to those skilled in the art can be utilized in the practice of the present invention. However, the preferred materials and methods are described herein. Unless otherwise indicated, materials, reagents and the like referred to in the following specification and examples may be obtained from commercial sources.

The definitions described herein can be concatenated to form chemically relevant combinations such as "heteroalkylaryl," "haloalkylheteroaryl," "arylalkyl heterocyclyl," "alkylcarbonyl," "alkoxyalkyl," and the like. When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl" or "hydroxyalkyl", it refers to an alkyl group, as defined above, substituted with one or two substituents selected from another group specifically named. Thus, for example, "phenylalkyl" refers to an alkyl group having one or two phenyl substituents, thereby including benzyl, phenylethyl, and biphenyl. "alkylaminoalkyl" is an alkyl group having one or two alkylamino substituents. "hydroxyalkyl" includes 2-hydroxyethyl, 2-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 2, 3-dihydroxybutyl, 2- (hydroxymethyl), 3-hydroxypropyl and the like. Thus, the term "hydroxyalkyl" as used herein is intended to define a subset of heteroalkyl groups as defined hereinafter. The term (ar) alkyl refers to an unsubstituted alkyl or aralkyl group. The term (hetero) aryl ((hetero) aryl or (het) aryl) refers to aryl or heteroaryl.

The term "spirocycloalkyl" as used herein refers to spirocyclic cycloalkyl groups, such as spiro [3.3] heptane. The term spiroheterocycloalkyl as used herein refers to spiroheterocycloalkyl, such as 2, 6-diazaspiro [3.3] heptane.

The term "acyl" as used herein denotes a group of formula-C (═ O) R, where R is hydrogen or lower alkyl as defined herein. The term "alkylcarbonyl" as used herein, denotes a group of formula C (═ O) R, wherein R is alkyl as defined herein. Term C_1-6Acyl refers to a-C (═ O) R group containing 6 carbon atoms. The term "arylcarbonyl" as used herein refers to a group of formula C (═ O) R, wherein R is aryl; the term "benzoyl" as used herein is an "arylcarbonyl" group wherein R is phenyl.

The term "ester" as used herein denotes a group of formula-C (═ O) OR, where R is lower alkyl as defined herein.

The term "alkyl" as used herein denotes an unbranched or branched, saturated, monovalent hydrocarbon radical containing from 1 to 10 carbon atoms. The term "lower alkyl" denotes a straight or branched chain hydrocarbon group containing 1 to 6 carbon atoms. As used herein, "C_1-10Alkyl "refers to an alkyl group consisting of 1 to 10 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl" or "hydroxyalkyl", it refers to an alkyl group, as defined above, substituted with one or two substituents selected from another group specifically named. Thus, for example, "phenylalkyl" means R 'R "-, where R' is phenyl and R" is alkylene as defined herein, meaning that the point of attachment of the phenylalkyl moiety is on the alkylene. Examples of arylalkyl groups include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. The term "arylalkyl" or "aralkyl" may be construed similarly, except that R' is aryl. The terms "(hetero) arylalkyl" or "(hetero) aralkyl" are to be construed analogously, except that R' is optionally aryl or heteroaryl.

The term "haloalkyl" or "halo-lower alkyl" or "lower haloalkyl" refers to a straight or branched chain hydrocarbon radical containing 1 to 6 carbon atoms, wherein one or more carbon atoms are substituted with one or more halogen atoms.

As used herein, unless otherwise indicated, the term "alkylene" or "alkylene" refers to a divalent saturated straight chain hydrocarbon radical having from 1 to 10 carbon atoms (e.g., (CH)₂)_n) Or a branched saturated divalent hydrocarbon radical having 2 to 10 carbon atoms (e.g. -CHMe-or-CH)₂CH(i-Pr)CH₂-). Except in the case of methylene, the free valences (open valences) of the alkylene groups are not attached to the same atom. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, 1-dimethyl-ethylene, butylene, 2-An ethyl butylene group.

The term "alkoxy" as used herein refers to an-O-alkyl group, wherein alkyl is as defined above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, including isomers thereof. "lower alkoxy" as used herein denotes alkoxy having "lower alkyl" as defined above. As used herein, "C_1-10Alkoxy "refers to-O-alkyl wherein alkyl is C_1-10。

The term "PCy₃"refers to a phosphine trisubstituted with three ring moieties.

The term "haloalkoxy" or "halo-lower alkoxy" or "lower haloalkoxy" refers to lower alkoxy wherein one or more carbon atoms are substituted with one or more halogen atoms.

The term "hydroxyalkyl" as used herein denotes an alkyl group as defined herein wherein 1 to 3 hydrogen atoms on different carbon atoms are replaced by a hydroxyl group.

The terms "alkylsulfonyl" and "arylsulfonyl" as used herein refer to the formula S (═ O)₂R, wherein R is independently alkyl or aryl and alkyl and aryl are as defined herein. The term "heteroalkylsulfonyl" as used herein, refers to a compound of formula-S (═ O)₂The group of R, wherein R is "heteroalkyl" as defined above.

The terms "alkylsulfonylamino" and "arylsulfonylamino" as used herein refer to the formula-NR' S (═ O)₂R' is hydrogen or C_1-3Alkyl, and alkyl and aryl are as defined herein.

The term "cycloalkyl" as used herein refers to a saturated carbocyclic ring containing from 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. As used herein, "C_3-7Cycloalkyl "refers to a ring formed by a carbocyclic ringCycloalkyl with 3-7 carbons in the ring.

The term "carboxy-alkyl" as used herein refers to an alkyl moiety wherein one hydrogen atom is replaced by a carboxy group, wherein the point of attachment of the heteroalkyl group is a carbon atom. The term "carboxy" (or carboxyl) refers to-CO₂And (4) a H part.

The term "heteroaryl" or "heteroaromatic" as used herein refers to a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic or partially unsaturated ring, each ring containing 4 to 8 atoms, incorporating one or more N, O or S heteroatoms, the other ring atoms being carbon, wherein 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 are less aromatic than their corresponding all-carbon rings. Thus, for the purposes of the present invention, heteroaryl groups need only have some degree of aromaticity. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms, including, but not limited to, pyridyl, pyrimidinyl, pyrazinyl, oxazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, 4, 5-dihydro-oxazolyl, 5, 6-dihydro-4H- [1,3] oxazolyl, isoxazole, thiazole, isothiazole, triazoline, thiadiazole and oxadiazoline (oxadixoline), which may be optionally substituted with one or more, preferably one or two substituents selected from the group consisting of: hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoxazole, benzisoxazole, benzothiazole, naphthyridinyl, 5,6,7, 8-tetrahydro- [1,6] naphthyridinyl, and benzisothiazole. The bicyclic moiety may be optionally substituted on either ring, but the point of attachment is on the ring containing the heteroatom.

As used herein, unless otherwise indicated, the terms "heterocyclyl", "heterocycloalkyl" or "heterocycle" mean a monovalent saturated cyclic group consisting of one or more rings, preferably one to two rings (including spiro ring systems), with 3-8 atoms per ring, incorporating one or more ring heteroatoms selected from N, O or S (O)_0-2) And which may optionally be independently substituted by one or more, preferably one or two, substituents selected from: hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, and ionic forms thereof. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl, and imidazolinyl and ionic forms thereof. Examples may also be bicyclic, e.g. 3, 8-diaza-bicyclo [3.2.1]Octane, 2, 5-diaza-bicyclo [2.2.2]Octane or octahydro-pyrazino [2,1-c][1,4]Oxazines.

SYK inhibitors

The formula I shown in the application:

intended to include structural formulae having the following pyridazine ring resonance arrangement:

the application provides compounds of formula I

Wherein:

a is cycloalkyl or heterocycloalkyl;

each R is independently H or R';

each R "is independently hydroxy, lower alkylamido, carboxy, oxo, lower alkoxy, lower alkylamino, or lower dialkylamino;

m is 0, 1 or 2;

b is phenyl or a monocyclic or bicyclic heteroaryl;

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

The present application provides compounds of formula (I) wherein B is pyridyl.

The present application provides compounds of formula (I) wherein a is cyclohexyl or tetrahydropyranyl.

The present application provides compounds of formula (I) wherein a is cyclohexyl.

The present application provides compounds of formula (I) wherein a is tetrahydropyranyl.

The present application provides compounds of formula (I) wherein a is cyclohexyl or tetrahydropyranyl and B is pyridinyl.

The present application provides compounds of formula (I) wherein a is cyclohexyl and B is pyridinyl.

The present application provides compounds of formula (I) wherein a is tetrahydropyranyl and B is pyridinyl.

The present application provides compounds of formula (I) wherein m is 1.

The present application provides compounds of formula (I) wherein a is cyclohexyl, B is pyridinyl, and m is 1.

The present application provides compounds of formula (I) wherein a is tetrahydropyranyl, B is pyridinyl, and m is 1.

The present application provides compounds of formula (I) wherein X is amino.

The present application provides compounds of formula (I) wherein a is cyclohexyl, B is pyridinyl, m is 1, and X is amino.

The present application provides compounds of formula (I) wherein a is tetrahydropyranyl, B is pyridinyl, m is 1, and X is amino.

The present application provides compounds of formula (I) wherein n is 1.

The present application provides compounds of formula (I) wherein a is cyclohexyl, B is pyridinyl, m is 1, X is amino, and n is 1.

The present application provides compounds of formula (I) wherein a is tetrahydropyranyl, B is pyridinyl, m is 1, X is amino, and n is 1.

The present application provides compounds of formula (I) wherein each Y is independently halogen, lower alkyl, lower alkoxy, lower hydroxyalkyl, heteroaryl, lower alkylsulfonyl, cycloalkyl or heteroaryl.

The present application provides compounds of formula (I) wherein Y is lower alkyl, cycloalkyl, heteroaryl or lower alkylsulfonyl.

The present application provides compounds of formula (I) wherein Y is lower alkyl.

The present application provides compounds of formula (I) wherein a is cyclohexyl, B is pyridinyl, m is 1, X is amino, n is 1, and Y is lower alkyl.

The present application provides compounds of formula (I) wherein a is tetrahydropyranyl, B is pyridinyl, m is 1, X is amino, n is 1, and Y is lower alkyl.

The present application provides compounds of formula (I) wherein n is 2.

The present application provides compounds of formula (I) wherein a is cyclohexyl, B is pyridinyl, m is 1, X is amino, and n is 2.

The present application provides compounds of formula (I) wherein a is tetrahydropyranyl, B is pyridinyl, m is 1, X is amino, and n is 2.

The present application provides compounds of formula (I) wherein one Y is lower alkyl and the other is halogen or lower alkyl.

The present application provides compounds of formula (I) wherein a is cyclohexyl, B is pyridinyl, m is 1, X is amino, n is 2, one Y is lower alkyl and the other is halogen or lower alkyl.

The application provides compounds of formula (I) wherein a is tetrahydropyranyl, B is pyridinyl, m is 1, X is amino, n is 2, one Y is lower alkyl and the other is halogen or lower alkyl.

The present application provides compounds of formula (I) wherein B is pyrrolo [2,3-B ] pyridinyl or pyrazolyl.

The present application provides compounds of formula (I) wherein B is pyrrolo [2,3-B ] pyridinyl.

The present application provides compounds of formula (I) wherein B is pyrazolyl.

The present application provides compounds of formula (I) wherein a is cyclohexyl, B is pyrrolo [2,3-B ] pyridinyl, m is 1, X is amino, n is 1, and Y is lower alkyl.

The present application provides compounds of formula (I) wherein a is cyclohexyl, B is pyrazolyl, m is 1, X is amino, n is 1, and Y is lower alkyl.

The present application provides a compound selected from the group consisting of:

6- (cis-2-amino-cyclohexylamino) -4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxylic acid amide;

6- (cis-2-amino-cyclohexylamino) -4- (6-ethyl-pyridin-2-ylamino) -pyridazine-3-carboxylic acid amide;

6- ((3R,4R) -3-amino-tetrahydropyran-4-ylamino) -4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide;

6- ((1S,2R) -2-amino-cyclohexylamino) -4- (6- [1,2,3] triazol-1-yl-pyridin-2-ylamino) -pyridazine-3-carboxamide;

6- (cis-2-amino-cyclohexylamino) -4- (5-methanesulfonyl-pyridin-2-ylamino) -pyridazine-3-carboxylic acid amide;

6- ((1R,2S) -2-amino-cyclohexylamino) -4-p-tolylamino-pyridazine-3-carboxamide;

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (6-isopropyl-pyridin-2-ylamino) -pyridazine-3-carboxamide;

6- ((3R,4R) -3-amino-tetrahydropyran-4-ylamino) -4- (5, 6-dimethyl-pyridin-2-ylamino) -pyridazine-3-carboxamide;

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (1-methyl-1H-pyrazol-3-ylamino) -pyridazine-3-carboxamide;

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide;

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-ylamino) -pyridazine-3-carboxamide;

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (6-cyclopropyl-pyridin-2-ylamino) -pyridazine-3-carboxamide;

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (5-fluoro-6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide;

6- ((1S,2R) -2-amino-cyclohexylamino) -4- (6-ethyl-pyridin-2-ylamino) -pyridazine-3-carboxamide;

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (5, 6-dimethyl-pyridin-2-ylamino) -pyridazine-3-carboxamide;

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (5-chloro-6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide;

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (5, 6-dimethoxy-pyridin-2-ylamino) -pyridazine-3-carboxamide;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (4, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide 2,2, 2-trifluoroacetate salt;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-tert-butylpyridin-2-ylamino) pyridazine-3-carboxamide;

6- (cyclohexylamino) -4- (6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-cyclobutylpyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (1-methyl-1H-benzo [ d ] imidazol-4-ylamino) pyridazine-3-carboxamide;

4- (6- (2H-1,2, 3-triazol-2-yl) pyridin-2-ylamino) -6- ((1R,2S) -2-aminocyclohexylamino) pyridazine-3-carboxamide;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6, 7-dihydro-5H-cyclopenta [ b ] pyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (6-isopropyl-5-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-propylpyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((3R,4R) -3-amino-tetrahydropyran-4-ylamino) -4- (6-isopropyl-5-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (3, 5-dimethylphenylamino) pyridazine-3-carboxamide;

6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (6-tert-butylpyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-ethoxypyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine-3-carboxamide;

4- (6- (1H-pyrazol-1-yl) pyridin-2-ylamino) -6- ((1R,2S) -2-aminocyclohexylamino) pyridazine-3-carboxamide;

6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-isopropyl-4-methylpyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((1R,2S) -2-aminocyclohexylamino) -4- (4-methyl-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (4-methyl-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (5-fluoro-6-isopropylpyridin-2-ylamino) pyridazine-3-carboxamide;

6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (5-isopropyl-6-methoxypyridin-2-ylamino) pyridazine-3-carboxamide; and

6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (6-isopropoxypyridin-2-ylamino) pyridazine-3-carboxamide.

The present application provides the above method further comprising administering an additional therapeutic agent selected from the group consisting of: chemotherapeutic or antiproliferative agents, anti-inflammatory agents, immunomodulatory or immunosuppressive agents, neurotrophic factors, agents for treating cardiovascular disease, agents for treating diabetes, or agents for treating immunodeficiency.

The present application provides a method of treating an inflammatory disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.

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.

The present 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 present application provides methods of treating immune disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, including lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications of organ transplantation, xenotransplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, crohn's disease, alzheimer's disease, and leukemia.

The present application provides a method of treating an inflammatory disorder comprising co-administering to a patient in need thereof a therapeutically effective amount of a combination of an anti-inflammatory compound and a compound of formula I.

The present application provides a method of treating an immune disorder comprising co-administering to a patient in need thereof a therapeutically effective amount of a combination of an immunosuppressive compound and a compound of formula I.

The present application provides compositions comprising a compound of formula I in admixture with at least one pharmaceutically acceptable carrier, excipient or diluent.

The present application provides the above pharmaceutical composition, further comprising an additional agent selected from the group consisting of: chemotherapeutic or antiproliferative agents, anti-inflammatory agents, immunomodulatory or immunosuppressive agents, neurotrophic factors, agents for treating cardiovascular disease, agents for treating diabetes, and agents for treating immunodeficiency.

The present application provides the use of a compound of formula I in the manufacture of a medicament for the treatment of disorders associated with Syk.

The application provides the use of a compound of formula I in the manufacture of a medicament for the treatment of rheumatoid arthritis.

A compound, method or composition as described herein.

Examples of representative compounds encompassed by and within the scope of the present invention are provided in the following table. These examples and the subsequent preparations are provided so that those skilled in the art can more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

In general, the nomenclature used in the present invention is based on AUTONOMTM v.4.0 (a BeilsteinInstitute computerized system) or architecture (a name)Application) was used to generate IUPAC systematic nomenclature. If the depicted structure is not consistent with the name given to that structure, the depicted structure shall control. Furthermore, if the stereochemistry of a structure or a portion of a structure is not indicated, for example, with bold or underline, it should be interpreted to encompass all stereoisomers of it.

Table I describes examples of triazolopyridine compounds of general formula I.

TABLE I

Synthesis of

General scheme

A compound of the general formula I

Wherein:

a is cycloalkyl or heterocycloalkyl;

each R is independently H or R';

m is 0, 1 or 2;

b is heteroaryl;

each Y is independently halogen, lower alkyl, lower alkoxy, lower haloalkyl, lower hydroxyalkyl, heteroaryl, lower alkylsulfonyl, or heterocycloalkyl; and is

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof, can be synthesized according to the following general scheme:

wherein Y is as defined above, Q may be CH or N, and Z may be CH₂Or O, and R¹May be a lower alkyl group.

Pharmaceutical compositions and administration

The compounds of the present invention may be formulated in a variety of oral dosage forms and carriers. The oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions, syrups or suspensions. The compounds of the present invention are effective when administered by other routes of administration, including continuous (intravenous drip) topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancer), buccal, nasal, inhalation, and suppository administration, and the like. The preferred mode of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient.

The compounds of the present invention and their pharmaceutically acceptable salts may be formulated into pharmaceutical compositions and unit dosage forms with one or more conventional excipients, carriers, or diluents. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or substances, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be used as solids (e.g., tablets or filled capsules), semisolids, powders, sustained release formulations, or liquids (e.g., solutions, suspensions, emulsions, elixirs, or oral filled capsules); or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Typical formulations will contain from about 5% to about 95% active compound (w/w). The term "formulation" or "dosage form" includes both solid and liquid formulations of the active compound, and those skilled in the art will understand that the active ingredient can be present in different formulations depending on the target organ or tissue and depending on the desired dosage and pharmacokinetic parameters.

The term "excipient", as used herein, refers to a compound used in the preparation of pharmaceutical compositions, which are generally safe, non-toxic and neither biologically nor otherwise undesirable, and which include veterinary and human pharmaceutically acceptable excipients. The compounds of the present invention can be administered alone, but will generally be administered in admixture with 1 or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.

By "pharmaceutically acceptable" it is meant that it is useful in the preparation of pharmaceutical compositions that are generally safe, non-toxic and neither biologically nor otherwise undesirable, and that include veterinary as well as human pharmaceutical uses.

The "pharmaceutically acceptable salt" form of the active ingredient may also initially impart desirable pharmacokinetic properties not found in the non-salt form of the active ingredient, and may even positively affect the pharmacodynamics of the active ingredient with respect to its in vivo therapeutic activity. The phrase "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. The salt comprises: (1) formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like) or with organic acids (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, dodecylsulfuric acid, and the like), Gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.); or (2) salts formed when the acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, alkaline earth ion, or aluminum ion) or is coordinated to an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like).

Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include, without limitation, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. In addition to the active ingredients, solid form preparations may contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

Liquid preparations are also suitable for oral administration and include emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted, prior to use, to liquid form preparations. Emulsions may be prepared in solution, for example in aqueous propylene glycol solution, or they may contain emulsifying agents, for example lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents.

The compounds of the invention may be formulated for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion) and they may be in unit dosage form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example, as solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and which may contain formulatory agents such as preservatives, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use, by aseptic isolation of sterile solid or by lyophilization from solution.

The compounds of the invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. For example, ointments and creams may be formulated with an aqueous or oily base to which suitable thickening and/or gelling agents are added. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include: lozenges comprising the active agent in a flavored base (usually sucrose and acacia or tragacanth); pastilles comprising the active ingredient in an inert base (e.g. gelatin and glycerin or sucrose and acacia); and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated for administration as suppositories. The low melting wax (e.g., a mixture of fatty acid glycerides and cocoa butter) is first melted and the active ingredient is dispersed uniformly, such as by stirring. The molten homogeneous mixture is then poured into a mold of conventional size, allowed to cool and solidify.

The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers in addition to the active ingredient are known in the art to be suitable.

The compounds of the present invention may be formulated for nasal administration. Solutions and suspensions may be applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or nebulizer. The formulations may be provided in single or multiple dose forms. In the latter case of a dropper or pipette, this may be achieved by the patient administering a suitable, predetermined volume of solution or suspension. In the case of a nebulizer, this can be achieved, for example, by a metered nebulization spray pump.

The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract, and include intranasal administration. The compounds typically have a small particle size, for example, on the order of 5 microns or less. The particle size may be obtained by methods known in the art, for example by micronisation. The active ingredient is provided in pressurized packs with a suitable propellant, e.g., a chlorofluorocarbon (CFC), e.g., dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may also suitably contain a surfactant, for example lecithin. The dosage of the drug can be controlled by a metering valve. Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. The powder compositions may be in unit dosage form, for example in capsules or cartridges such as gelatin or blister packs, from which the powder may be administered by means of an inhaler.

When desired, the formulations can be prepared with enteric coatings suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated into transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with the treatment regimen is critical. The compounds in transdermal delivery systems are often attached to a solid support that adheres to the skin. The compound of interest can also be combined with a penetration enhancer such as azone (1-dodecylaza-cycloheptan-2-one). The sustained release drug delivery system is inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate compounds in a lipid soluble film (e.g., silicone rubber) or a biodegradable polymer (e.g., polylactic acid).

Suitable formulations with pharmaceutical carriers, diluents and excipients are described in Remington, edited by e.w. martin, The Science and Practice of Pharmacy1995, mack publishing Company, 19 th edition, Easton, pa. The skilled formulation scientist, given the teachings of the specification, will vary the formulation to provide a wide variety of formulations for a particular route of administration without destabilizing or otherwise compromising the therapeutic activity of the compositions of the present invention.

For example, it is within the ordinary skill in the art that the compounds of the present invention can be readily modified to be more stable in water or other vehicles by minor modifications (salt formation, esterification, etc.). The route of administration and dosage regimen of a particular compound may be varied in order to control the pharmacokinetics of the compounds of the present invention and thereby maximize the beneficial effects in the patient, and is also within the ordinary skill in the art.

The term "therapeutically effective amount" as used herein refers to the amount required to reduce the symptoms of a disease in an individual. The dosage is adjusted according to the individual requirements in each particular case. The dosage can vary within wide limits depending on a number of factors, such as the severity of the disease being treated, the age and general health of the patient, other drugs being used while the patient is being treated, the route and form of administration, and the preferences and experience of the attending physician. For oral administration, daily dosages between about 0.01 to about 1000mg/kg body weight per day should be suitable for monotherapy and/or combination therapy. A preferred daily dosage is between about 0.1 and about 500mg/kg body weight, more preferably between about 0.1 and about 100mg/kg body weight per day, and most preferably between about 1.0 and about 10mg/kg body weight per day. Thus, for administration to a 70kg human, the dosage range will be about 7mg to 0.7g per day. The daily dose can be administered as a single dose or in divided doses, usually between 1 and 5 administrations per day. Typically, treatment is initiated at smaller doses than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimum effect is achieved for each patient. The ordinarily skilled artisan in treating the diseases described herein will be able to determine, without undue experimentation and relying on his or her personal knowledge, experience, and content of the present application, a therapeutically effective amount of a compound of the present invention for a given disease and patient.

The pharmaceutical formulation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged preparation, the package containing a discrete number of the preparation, for example, tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Preparation

Pharmaceutical formulations delivered by various routes were formulated as shown in the following table. The "active ingredient" or "active compound" used in the tables refers to one or more compounds of formula I.

Composition for oral administration

Composition (I)	% weight/weight
		Active ingredient	20.0％
Lactose	79.5％
		Magnesium stearate	0.5％

Mixing and dispensing the ingredients into capsules, each capsule containing about 100 mg; one capsule is about the total daily dose.

Composition for oral administration

Composition (I)	% weight/weight
		Active ingredient	20.0％
Magnesium stearate	0.5％
		Croscarmellose sodium	2.0％
Lactose	76.5％
		PVP (polyvinylpyrrolidone)	1.0％

The ingredients are mixed and granulated using a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20mg of active compound) using a suitable tablet press.

Composition for oral administration

Composition (I)	Measurement of
		Active compound	1.0g
Fumaric acid	0.5g
		Sodium chloride	2.0g
P-hydroxybenzoic acid methyl ester	0.15g
		Propyl p-hydroxybenzoate	0.05g
Granulated sugar	25.5g
		Sorbitol (70% solution)	12.85g
Veegum K(Vanderbilt Co.)	1.0g
		Flavoring agent	0.035ml
Coloring agent	0.5mg
		Distilled water	Enough to 100ml

These ingredients are mixed to form a suspension for oral administration.

Parenteral formulation

Composition (I)	% weight/weight
		Active ingredient	0.25g
Sodium chloride	Proper amount to equal sheet
		Water for injection	100ml

These active ingredients were dissolved in a portion of the water for injection. Sufficient sodium chloride is then added with stirring to make the solution isotonic. The solution was then made up to capacity with the remaining water for injection, filtered through a 0.2 μm membrane filter and packaged under sterile conditions.

Suppository formulation

Composition (I)	% weight/weight
		Active ingredient	1.0％
Polyethylene glycol 1000	74.5％
		Polyethylene glycol 4000	24.5％

The ingredients were melted and mixed on a steam bath and then poured into molds containing a total weight of 2.5 g.

Topical formulations

Composition (I)	Keke (Chinese character of 'Keke')
		Active compound	0.2-2
Span60 (Span60)	2
		Tween 60	2
Mineral oil	5
		Vaseline	10
P-hydroxybenzoic acid methyl ester	0.15
		Propyl p-hydroxybenzoate	0.05
BHA (butylated hydroxyanisole)	0.01
		Water (W)	Proper amount 100

All of the ingredients (except water) were mixed and heated to 60 ℃ with stirring. Sufficient water at about 60 c is then added to emulsify these ingredients under vigorous stirring, followed by the addition of a suitable amount of about 100g of water.

Nasal spray

Several aqueous suspensions containing about 0.025-0.5% active compound are formulated as nasal sprays. These formulations optionally contain inactive ingredients, for example, microcrystalline cellulose, sodium carboxymethylcellulose, glucose, and the like. Hydrochloric acid may be added to adjust the pH. These nasal sprays can be delivered via a nasal spray metering pump, typically about 50-100ml of formulation per actuation. A typical dosing regimen is 2-4 puffs every 4-12 hours.

Indications and treatment methods

The compounds described herein are kinase inhibitors, particularly SYK inhibitors. These inhibitors are useful for treating one or more diseases responsive to kinase inhibition in a mammal, including diseases responsive to SYK inhibition and/or B-cell proliferation inhibition. Without wishing to be bound by any particular theory, it is believed that the interaction of the compounds of the present invention with SYK results in the inhibition of SYK activity, thereby achieving the pharmaceutical utility of these compounds. Accordingly, the present invention includes a method of treating a mammal, such as a human, having a disease responsive to inhibition of SYK activity and/or inhibition of B-cell proliferation, comprising administering to the mammal having the disease a therapeutically effective amount of at least one chemical entity provided herein. Effective concentrations can be determined experimentally, for example by analyzing the blood concentration of the compound or theoretically by calculating bioavailability. In addition to SYK, other kinases that may be affected include, but are not limited to, other tyrosine kinases and serine/threonine kinases.

Kinases play a significant role in signal transduction pathways that control basic cellular processes such as proliferation, differentiation, and death (apoptosis). Abnormal kinase activity is implicated in a variety of diseases, including a variety of cancers, autoimmune and/or inflammatory diseases, and acute inflammatory responses. The multifaceted role of kinases in key cellular signaling pathways provides an important opportunity to identify novel drugs that target kinases and signaling pathways.

The present application provides the above method further comprising administering an additional therapeutic agent selected from the group consisting of: chemotherapeutic or antiproliferative agents, anti-inflammatory agents, immunomodulatory or immunosuppressive agents, neurotrophic factors, agents for treating cardiovascular disease, agents for treating diabetes, or agents for treating immunodeficiency disorders.

The present application provides methods of treating immune disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, including lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, organ transplantation, allograft complications, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, crohn's disease, alzheimer's disease, and leukemia.

The present application provides a method of treating an inflammatory disorder comprising co-administering to a patient in need thereof a therapeutically effective amount of an anti-inflammatory compound in combination with a compound of formula I.

The present application provides methods of treating an immune disorder comprising administering to a patient in need thereof a therapeutically effective amount of an immunosuppressive compound in combination with a compound of formula I.

Examples

Abbreviations

Common abbreviations include: common abbreviations include: acetyl (Ac), azo-bis-isobutyronitrile (AIBN), atmospheric pressure (Atm), 9-borabicyclo [3.3.1]Nonane (9-BBN or BBN), 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl(BINAP), tert-butoxycarbonyl (Boc), di-tert-butyl dicarbonate or Boc anhydride (Boc)₂O), benzyl (Bn), butyl (Bu), chemical Abstract registry number (CASRN), benzyloxycarbonyl (CBZ or Z), Carbonyldiimidazole (CDI), 1, 4-diazabicyclo [2.2.2]Octane (DABCO), diethylaminosulfur trifluoride (DAST), dibenzylidene acetone (dba), 1, 5-diazabicyclo [4.3.0]Non-5-ene (DBN), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU), N ' -Dicyclohexylcarbodiimide (DCC), 1, 2-Dichloroethane (DCE), Dichloromethane (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-Dimethylacetamide (DMA), 4-N, N-Dimethylaminopyridine (DMAP), N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1' -bis- (diphenylphosphino) ethane (dppe), 1' -bis- (diphenylphosphino) ferrocene (dppf), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-1-carboxylic acid Ethyl Ester (EEDQ), diethyl ether (Et)₂O), Ethyl isopropyl ether (EtOiPr), O- (7-azabenzotriazol-1-yl) -N, N, N 'N' -tetramethyluronium hexafluorophosphate acetic acid (HATU), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), High Pressure Liquid Chromatography (HPLC), Isopropanol (IPA), isopropyl magnesium chloride (iPrMgCl), Hexamethyldisilazane (HMDS), Liquid Chromatography Mass Spectrometry (LCMS), lithium hexamethyldisilazane (LiHMDS), m-chloroperoxybenzoic acid (m-CPBA), methanol (MeOH), melting point (mp), MeSO₂- (methylsulfonyl or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrometry (Ms), methyl tert-butyl ether (MTBE), methyltetrahydrofuran (MeTHF), N-bromosuccinimide (NBS), N-butyllithium (nBuLi), N-carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), dichloro- ((bis-diphenylphosphino) ferrocenyl) palladium (II) (Pd (dppf) Cl₂) Palladium (II) acetate (Pd (OAC)₂) Tris (dibenzylideneacetone) dipalladium (0) (Pd)₂(dba)₃) Pyridine Dichromate (PDC), phenyl (Ph),Propyl (Pr), isopropyl (i-Pr), pounds per square inch (psi), pyridine (pyr), 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphino) ferrocene (Q-Phos), room temperature (ambient temperature RT or RT), sec-butyllithium (sBuLi), tert-butyldimethylsilyl, or t-BuMe₂Si (TBDMS), tetra-n-butylammonium fluoride (TBAF), triethylamine (TEA or Et)₃N), 2,6, 6-tetramethylpiperidin-1-oxyl (TEMPO), trifluoromethanesulfonic group or CF₃SO₂- (Tf), trifluoroacetic acid (TFA), 1' -bis-2, 2,6, 6-tetramethylheptane-2, 6-dione (TMHD), O-benzotriazol-1-yl-N, N, N ', N ' -tetramethyluronium tetrafluoroborate (TBTU), Thin Layer Chromatography (TLC), Tetrahydrofuran (THF), trimethylsilyl or Me₃Si (TMS), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C6H₄SO₂-or tosyl (Ts), N-urethane-N-carboxy anhydride (UNCA). The customary Nomenclature (including the prefixes positive (n), iso (i-), secondary (sec-), tertiary (tert-), and neo) have their customary meaning when used with alkyl moieties (j.rigaudy and d.p.klesney, Nomenclature in Organic Chemistry, IUPAC1979 pergammonpress, Oxford.).

General conditions

Unless otherwise indicated, all temperatures, including melting points (i.e., MP) are in degrees Celsius (. degree. C.). It is to be understood that the reaction that produces the indicated and/or desired product may not necessarily result from the combination of two reagents that are initially added, i.e., it may be one or more intermediates that are produced in the mixture that ultimately results in the formation of the indicated and/or desired product. The foregoing abbreviations may be used in the preparations and examples. All names were generated using Autonom or ChemDraw.

The following preparations and examples are given to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Preparation examples

Example 1

6- (cis-2-amino-cyclohexylamino) -4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide

A mixture of 6-chloro-4- (6-methylpyridin-2-ylamino) pyridazine-3-carboxamide (0.0996g, 0.378mmol), N-methylpyrrolidone (2mL) and racemic cis-cyclohexane-1, 2-diamine (0.270mL, 2.29mmol) was stirred at 150 ℃ for 15 hours and then concentrated to a dark orange oil. By chromatography (silica gel, 0-10% 20:1 methanol: NH)₄A mixture of OH in dichloromethane) to give an orange solid. The solid was triturated with a mixture of methanol (1mL) and diethyl ether (10mL), then filtered and dried to give 6- (cis-2-amino-cyclohexylamino) -4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide (0.041g, 32%) as a light brown solid.¹H NMR(300MHz，DMSO-d₆) ppm1.33(d, J ═ 9.06Hz,2H),1.47-1.79(M,6H),2.13(br.s.,2H),3.16(d, J ═ 3.02Hz,1H),3.89(br.s.,1H),6.74(d, J ═ 8.31Hz,1H),6.79-6.89(M,2H),7.52-7.67(M,2H),8.09(s,1H),8.35(br.s.,1H),11.59(s,1H) (pyridylmethyl peak, 3H, believed to coincide with DMSO solvent peak.) MS (EI/CI) M/z 342[ M + H ] 342[ M + H].

Example 2

A mixture of 6-chloro-4- (6-ethylpyridin-2-ylamino) pyridazine-3-carboxamide (0.0448g, 0.161mmol), N-methylpyrrolidone (1mL) and racemic cis-cyclohexane-1, 2-diamine (0.115mL, 0.977mmol) was stirred at 150 ℃ for 19h, then cooled and concentrated in vacuo. Passing colorPurification by chromatography (silica gel, 0-10% 20:1 methanol: NH4OH in dichloromethane) afforded a yellow solid. The solid was triturated with ether (5mL), filtered and dried to give racemic 6- (cis-2-amino-cyclohexylamino) -4- (6-ethyl-pyridin-2-ylamino) -pyridazine-3-carboxylic acid (0.0264g, 46%) as an off-white solid.¹H NMR(300MHz,DMSO-d₆)ppm1.26(t,J＝7.55Hz,5H),1.43-1.79(m,8H),2.74(q,J＝7.43Hz,2H),3.11(br.s.,1H),3.78(br.s.,1H),6.71-6.81(m,2H),6.85(d,J＝7.55Hz,1H),7.55-7.68(m,2H),8.07(s,1H),8.36(br.s.,1H),11.65(s,1H).MS(EI/CI)m/z:356[M+H].

Example 3

6- ((3R,4R) -3-amino-tetrahydropyran-4-ylamino) -4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide

Step 1

6-chloro-4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide (150mg, 0.57mmol) and tert-butyl (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamate (185mg, 0.85mmol) were dissolved in 1, 4-dioxane (2.8mL) and N, N-diisopropylethylamine (0.25mL, 1.4 mmol). The reaction mixture was stirred at 150 ℃ for 4 days. Then (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamic acid tert-butyl ester (50mg, 0.23mmol) and N, N-diisopropylethylamine (0.04mL, 0.23mmol) were added in four portions (one portion per 36 hours for 144 hours). The mixture was cooled, then water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After concentration, the residue was purified by chromatography (silica gel, 0-7% methanol in dichloromethane) to give { (3R,4R) -4- [ 6-carbamoyl-5- (6-methyl-pyridin-2-ylamino) -pyridazin-3-ylamino ] -tetrahydropyran-3-yl } -carbamic acid tert-butyl ester (60mg, 18%) as a clear amorphous residue. It was 83% pure and used without further purification. MS (EI/CI) M/z:444[ M + H ].

Step 2

Tert-butyl (3R,4R) -4- (6-carbamoyl-5- (6-methylpyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamate (60mg, 83% pure, 0.112mmol) was dissolved in dichloromethane (0.85mL) and cooled to 0 ℃. Trifluoroacetic acid (0.35mL, 4.49mmol) was added dropwise and the mixture was then warmed to room temperature. After 3 hours, the mixture was concentrated in vacuo, then water, sodium bicarbonate and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate. To the aqueous layer was added sodium chloride, which was further extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by chromatography (silica gel, 0-10% methanol in dichloromethane) gave 6- ((3R,4R) -3-amino-tetrahydropyran-4-ylamino) -4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide (11mg, 28%) as an off-white solid.¹H NMR(300MHz,DMSO-d₆)ppm11.61(s,1H)8.39(br.s.,1H)8.12(s,1H)7.65(br.s.,1H)7.60(t,J＝7.7Hz,1H)6.95(d,J＝7.2Hz,1H)6.85(d,J＝7.6Hz,1H)6.75(d,J＝8.3Hz,1H)4.10(br.s.,1H)3.79-3.89(m,1H)3.66-3.75(m,1H)3.49-3.57(m,1H)3.37-3.47(m,1H)3.00-3.08(m,1H)1.94-2.12(m,1H)1.76-1.92(m,1H)1.63-1.73(m,1H).MS(EI/CI)m/z:344[M+H].

Example 4

6- ((1S,2R) -2-amino-cyclohexylamino) -4- (6- [1,2,3] triazol-1-yl-pyridin-2-ylamino) -pyridazine-3-carboxamide

Step 1

6- (di-tert-butyloxycarbonyl-amino) -2-bromopyridine (1.26g, 3.4mmol), copper powder (1.29g, 6.75mmol) and 1H-1,2, 3-trisOxazole (4.66g, 67.5mmol) and potassium hydroxide (0.38g, 6.75mmol) were combined and stirred at 130 ℃ for 16 hours. After cooling, the mixture was adsorbed onto silica gel and purified twice by chromatography (silica gel, 0-7% methanol in dichloromethane) and then (silica gel, 25-100% ethyl acetate in hexane) to give first 6- [1,2,3]Triazol-1-yl-pyridin-2-ylamine (203mg, 37%) as a white solid gave 6- [1,2, 3%]Triazol-2-yl-pyridin-2-ylamine (219mg, 40%) as a white solid. 6- [1,2,3]Triazol-1-yl-pyridin-2-ylamine:¹h NMR (300MHz, chloroform-d) ppm8.49(d, J ═ 1.1Hz,1H)7.80(d, J ═ 1.1Hz,1H)7.60-7.68(m,1H)7.51(d, J ═ 7.2Hz,1H)6.53(d, J ═ 7.9Hz, 1H); MS (EI/CI) M/z:162[ M + H [ ]]；6-[1,2,3]Triazol-2-yl-pyridin-2-ylamine:¹HNMR (300MHz, chloroform-d) ppm7.86(s,2H)7.62(t, J ═ 7.9Hz,1H)7.40(d, J ═ 7.9Hz,1H)6.52(d, J ═ 7.9Hz, 1H); MS (EI/CI) M/z:162[ M + H [ ]].

Step 2

4, 6-dichloro-pyridazine-3-carboxylic acid ethyl ester (200mg, 0.905mmol) and 6- [1,2,3]Triazol-1-yl-pyridin-2-ylamine (147mg, 0.914mmol) was dissolved in 1, 4-dioxane (6mL) and the solution was degassed with argon. Tris (dibenzylideneacetone) dipalladium (83mg, 0.09mmol), Xantphos (105mg, 0.18mmol) and cesium carbonate (884mg, 2.7mmol) were added and the reaction mixture was heated to 100 ℃ for 1 hour. The reaction mixture was cooled, diluted with saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by chromatography (silica gel, 25-100% ethyl acetate in hexane) afforded 6-chloro-4- (6- [1,2, 3)]Triazol-1-yl-pyridin-2-ylamino) -pyridazine-3-carboxylic acid ethyl ester (48mg, 15%) was a light yellow solid.¹HNMR (300MHz, chloroform-d) ppm9.34-9.43(m,1H)8.54-8.57(m,1H)8.43(d, J ═ 1.1Hz,1H)7.87-7.97(m,3H)7.60(dd, J ═ 7.4,1.3Hz,1H)4.55(q, J ═ 7.2Hz,2H)1.50(t, J ═ 7.2Hz, 3H); MS (EI/CI) M/z 346[ M + H ]].

Step 3

Ethyl 6-chloro-4- (6- [1,2,3] triazol-1-yl-pyridin-2-ylamino) -pyridazine-3-carboxylate (48mg, 0.139mmol) was suspended in 7M ammonia in methanol (23 mL). After 4h, the reaction mixture was concentrated in vacuo to give 6-chloro-4- (6- [1,2,3] triazol-1-yl-pyridin-2-ylamino) -pyridazine-3-carboxamide (44mg, 100%) as an off-white solid, which was used in the next step without purification. MS (EI/CI) M/z:317[ M + H ].

Step 4

Mixing 6-chloro-4- (6- [1,2, 3)]Triazol-1-yl-pyridin-2-ylamino) -pyridazine-3-carboxamide (44mg, 0.139mmol) was dissolved in N-methylpyrrolidinone (0.9 mL). Cis-cyclohexane-1, 2-diamine (95mg, 0.834mmol) was added and the mixture was warmed to 150 ℃. After 16h, the mixture was cooled and concentrated in vacuo. The obtained residue was diluted with a saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography (silica gel, 0:0:10-0.1:1:10 ammonium hydroxide: methanol: dichloromethane) gave 6- (cis-2-amino-cyclohexylamino) -4- (6- [1,2, 3)]Triazol-1-yl-pyridin-2-ylamino) -pyridazine-3-carboxamide (13mg, 23%) was a brown solid.¹H NMR(300MHz,DMSO-d₆)ppm10.33(s,1H)9.13(d,J＝8.3Hz,1H)8.84(d,J＝1.1Hz,1H)8.16-8.26(m,1H)8.03(d,J＝0.8Hz,1H)7.96(d,J＝7.9Hz,1H)7.67(s,1H)7.51-7.57(m,1H)7.51-7.57(m,1H)7.43-7.50(m,1H)3.60(br.s.,1H)2.96-3.03(m,1H)1.21-1.64(m,8H)；MS(EI/CI)m/z:395[M+H].

Example 5

6- (cis-2-amino-cyclohexylamino) -4- (5-methanesulfonyl-pyridin-2-ylamino) -pyridazine-3-carboxamide

Step 1

6-chloro-4- (5- (methylsulfonyl) pyridin-2-ylamino) pyridazine-3-carboxylic acid methyl ester

Into the flask were added methyl 4, 6-dichloropyridazine-3-carboxylate (200mg, 0.966mmol), 5- (methylsulfonyl) pyridin-2-amine (183mg, 1.06mmol), Pd₂(dba)₃(88.5mg, 0.097mmol), xanthphos (112mg, 0.193mmol) and cesium carbonate (944mg, 2.9 mmol). 1, 4-dioxane (6.0mL) was added and argon was bubbled through while the flask was sonicated for 5 minutes. The flask was sealed and heated at 100 ℃ for 1 hour. After cooling, the mixture was filtered through celite and CH₂Cl₂The filter cake is washed. The filtrate was concentrated in vacuo, then purified by chromatography (spherical silica gel 20-45 μ M,23 g, Versaflash Supelco, 0-100% ethyl acetate in hexanes for 30 min) to give methyl 6-chloro-4- (5- (methylsulfonyl) pyridin-2-ylamino) pyridazine-3-carboxylate (62mg, 19%) as a pale yellow solid.¹H NMR (400MHz, chloroform-d) ppm11.18(s,1H)9.31(s,1H)8.98(d, J ═ 2.27Hz,1H)8.19(dd, J ═ 8.59,2.53Hz,1H)7.09(dd, J ═ 8.84,0.76Hz,1H)4.15(s,3H)3.15(s,3H). LCMS (EI/CI) M/z 342.9[ M + H: (M, 1H): 342.9 ═ M].

Step 2

6-chloro-4- (5- (methylsulfonyl) pyridin-2-ylamino) pyridazine-3-carboxamide

Methyl 6-chloro-4- (5- (methylsulfonyl) pyridin-2-ylamino) pyridazine-3-carboxylate (62mg, 0.181mmol) was suspended in ammonia (7M in methanol, 3.94g, 5mL, 35.0 mmol). The reaction vessel was sealed. After 18 h, the mixture was concentrated in vacuo to give 6-chloro-4- (5- (methylsulfonyl) pyridin-2-ylamino) pyridazine-3-carboxamide (60mg, 100%) as an off-white solid, which was used in the next step without further purification.

Step 3

6- (cis-2-aminocyclohexylamino) -4- (5- (methylsulfonyl) pyridin-2-ylamino) pyridazine-3-carboxylic acid Amines as pesticides

A mixture of 6-chloro-4- (5- (methylsulfonyl) pyridin-2-ylamino) pyridazine-3-carboxamide (60mg, 0.183mmol), cis-cyclohexane-1, 2-diamine (125mg, 1.1mmol) and N-methyl-2-pyrrolidone (2mL) was heated to 150 ℃. After 18 hours, the reaction mixture was cooled and concentrated in vacuo. By chromatography (spherical silica gel 20-45uM, 23g, Versaflash Supelco, 0-5% 10% NH)₄OH CH of MeOH₂Cl₂Solution, 20 min) to give a solid residue. The residue was dissolved in MeOH and CH₂Cl₂And then precipitated by the addition of cyclohexane. The solid formed was obtained by decantation of the mother liquor and then dried to give 6- (cis-2-aminocyclohexylamino) -4- (5- (methylsulfonyl) pyridin-2-ylamino) pyridazine-3-carboxamide (19mg, 45.6 μmol, 25%) as a beige solid.¹H NMR(300MHz,DMSO-d₆)ppm12.21(s,1H)8.73(d,J＝2.27Hz,1H)8.48(br.s.,1H)8.16(s,1H)8.12(dd,J＝8.69,2.64Hz,1H)7.75(br.s.,1H)7.14(d,J＝8.69Hz,1H)7.03(d,J＝7.93Hz,1H)4.06(br.s.,1H)3.26(s,3H)3.09(br.s.,1H)1.24-1.78(m,10H).LCMS(EI/CI)m/z:406[M+H].

Example 6

6- ((1R,2S) -2-amino-cyclohexylamino) -4-p-tolylamino-pyridazine-3-carboxamide

Step 1

6-chloro-4-p-tolylamino-pyridazine-3-carboxylic acid methyl ester

Methyl 4, 6-dichloro-pyridazine-3-carboxylate (200mg, 0.966mmol), p-toluidine (104mg, 0.966mmol) and N, N-diiso-propy-latePropylethylamine (0.34mL, 1.93mmol) was dissolved in N, N-dimethylacetamide (2.4mL) and heated at 110 ℃ for 1 hour. The reaction mixture was cooled and then poured into ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, then the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by chromatography (silica gel, 0-50% ethyl acetate in hexanes) gave methyl 6-chloro-4-p-tolylamino-pyridazine-3-carboxylate (214mg, 79%) as an off-white solid.¹H NMR (300MHz, chloroform-d) ppm9.61(br.s.,1H)7.23-7.32(m,2H)7.13(d, J ═ 7.9Hz,2H)6.96(s,1H)4.08(s,3H)2.41(s, 3H); LCMS (EI/CI) M/z:278[ M + H].

Step 2

6-chloro-4-p-tolylamino-pyridazine-3-carboxamide

Methyl 6-chloro-4-p-tolylamino-pyridazine-3-carboxylate (210mg, 0.756mmol) was suspended in 7M ammonia in methanol (7 mL). After 3.5h, the reaction mixture was concentrated in vacuo to give 6-chloro-4- (6- [1,2,3] triazol-1-yl-pyridin-2-ylamino) -pyridazine-3-carboxamide (199mg, 100%) as an off-white solid, which was used in the next step without purification. MS (EI/CI) M/z:263[ M + H ].

Step 3

[ (1S,2R) -2- (6-carbamoyl-5-p-tolylamino-pyridazin-3-ylamino) -cyclohexyl]-carbamic acid Tert-butyl ester

6-chloro-4-p-tolylamino-pyridazine-3-carboxamide (199mg, 0.758mmol) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (325mg, 1.52mmol) were dissolved in N-methylpyrrolidone (4.7 mL). The reaction mixture was heated at 150 ℃ for 16h, then additional tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (550mg total, 2.57mmol) was added in three portions over 6 d. The reaction mixture was cooled, diluted with ethyl acetate and saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, then dried (sodium sulfate), filtered and concentrated in vacuo. The obtained residue was purified by chromatography (silica gel, 0-5% methanol in dichloromethane) to give [ (1S,2R) -2- (6-carbamoyl-5-p-tolylamino-pyridazin-3-ylamino) -cyclohexyl ] -carbamic acid tert-butyl ester (26mg, 8%) as a light brown amorphous residue. LCMS (EI/CI) M/z:441[ M + H ].

Step 4

6- ((1R,2S) -2-amino-cyclohexylamino) -4-p-tolylamino-pyridazine-3-carboxamide

Reacting [ (1S,2R) -2- (6-carbamoyl-5-p-tolylamino-pyridazin-3-ylamino) -cyclohexyl]Tert-butyl carbamate (26mg, 0.059mmol) is dissolved in dichloromethane (0.6mL) and then cooled to 0 ℃. Trifluoroacetic acid (0.27mL, 3.54mmol) was added dropwise and the reaction mixture was then warmed to 25 ℃. After 4 hours, the mixture was cooled in an ice bath and neutralized with sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. By chromatography (silica gel, 0-80% methanol 0.1: 0.01: NH)₄A solution of OH in dichloromethane) to give 6- ((1R,2S) -2-amino-cyclohexylamino) -4-p-tolylamino-pyridazine-3-carboxamide (15mg, 72%) as an off-white solid.¹H NMR(300MHz,DMSO-d₆)ppm10.30(s,1H)8.20-8.30(m,1H)7.44-7.55(m,1H)7.17-7.27(m,2H)7.07-7.17(m,2H)6.59(d,J＝7.9Hz,1H)6.33(s,1H)3.95-4.09(m,1H)2.93-3.06(m,1H)2.30(s,3H)1.19-1.68(m,9H)；LCMS(EI/CI)m/z:341[M+H].

Example 7

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (6-isopropyl-pyridin-2-ylamino) -pyridazine-3-carboxamide

Step 1

6-chloro-4- (6-isopropylpyridin-2-ylamino) pyridazine-3-carboxylic acid methyl ester

A stirred solution of methyl 4, 6-dichloropyridazine-3-carboxylate (255mg, 1.23mmol) and 6-isopropylpyridin-2-amine (252mg, 1.85mmol) in acetonitrile (8.0mL) was heated at 140 ℃ for 21 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo, then the residue was purified by chromatography (silica gel, 20-45 μm, 80g, Thomson, 0-10% acetone in dichloromethane, 20 min) to give methyl 6-chloro-4- (6-isopropylpyridin-2-ylamino) pyridazine-3-carboxylate (113mg, 30%) as a yellow solid.¹H NMR (400MHz, chloroform-d) ppm10.64(br.s.,1H)9.39(s,1H)7.63(t, J ═ 7.83Hz,1H)6.94(d, J ═ 7.58Hz,1H)6.78(d, J ═ 8.08Hz,1H)4.12(s,3H)3.01-3.19(M,1H)1.31-1.42(M,6H). LCMS (EI/CI) M/z 307[ M + H) M/z].

Step 2

6-chloro-4- (6-isopropylpyridin-2-ylamino) pyridazine-3-carboxamide

To a pressure tube was added methyl 6-chloro-4- (6-isopropylpyridin-2-ylamino) pyridazine-3-carboxylate (99mg, 322. mu. mol) followed by ammonia (7M in methanol, 3.94g, 5mL, 35.0 mmol). The mixture was heated to 50 ℃ for 18 hours, then additional 7N ammonia in methanol (7.5mL) was added. After 24 h, the mixture was cooled, filtered, and dried to give 6-chloro-4- (6-isopropylpyridin-2-ylamino) pyridazine-3-carboxamide (103mg, 100%) as a yellow solid.¹H NMR (400MHz, chloroform-d) ppm11.58(br.s.,1H)9.41(s,1H)8.20(br.s.,1H)7.60(t, J ═ 7.83Hz,1H)6.90(d, J ═ 7.33Hz,1H)6.77(d, J ═ 8.08Hz,1H)5.72(br.s.,1H)3.01-3.16(M,1H)1.37(d, J ═ 6.82Hz,6H) LCMS (EI/CI) M/z 292[ M + H ] M/z].

Step 3

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-isopropylpyridin-2-ylamino) pyridazine-3-carboxamide

To a solution of 6-chloro-4- (6-isopropylpyridin-2-ylamino) pyridazine-3-carboxamide (102mg, 350. mu. mol) in N-methyl-2-pyrrolidone (6ml) was added tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (150mg, 699. mu. mol), and the mixture was heated to 150 ℃ for 3 days. Additional tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (150mg, 699. mu. mol) was added and the reaction was heated to 150 ℃ for an additional 2 days, then cooled, concentrated and purified by chromatography (silica gel, 50. mu.m, 40g, Analogix, 96:3.8:0.2-84:15.2: 0.8; dichloromethane: MeOH: NH)₄OH) was purified to give a mixture of tert-butyl (1S,2R) -2- (6-carbamoyl-5- (6-isopropylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate and 6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-isopropylpyridin-2-ylamino) pyridazine-3-carboxamide (33 mg). The mixture was dissolved in dichloromethane (2mL) and TFA (370mg, 250. mu.L, 3.24mmol) was added. After 18 h, the mixture was concentrated in vacuo and chromatographed (spherical silica, 20-45 μm, 25g, Versaflash Supelco, 96:3.8:0.2-84:15.2:0.8 dichloromethane: MeOH: NH)₄OH, 25 min gradient) to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-isopropylpyridin-2-ylamino) pyridazine-3-carboxamide (12mg, 9%) as a brown solid.¹H NMR (400MHz, chloroform-d) ppm11.35(br.s.,1H)8.33(s,1H)7.96(br.s.,1H)7.44(t, J ═ 7.83Hz,1H)6.70(d, J ═ 7.58Hz,1H)6.61(d, J ═ 8.08Hz,1H)5.61(br.s.,1H)5.31(br.s.,1H)3.75(br.s.,1H)3.19(d, J ═ 3.28Hz,1H)2.89-3.01(M,1H)1.32-1.80(M,8H)1.27(d, J ═ 6.82Hz,6H) s (lcm/CI) M/z 370H + 370M/z].

Example 8

6- ((3R,4R) -3-amino-tetrahydropyran-4-ylamino) -4- (5, 6-dimethyl-pyridin-2-ylamino) -pyridazine-3-carboxamide

Step 1

6-chloro-4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

To the pressure tube was added a solution of 4, 6-dichloropyridazine-3-carboxylic acid ethyl ester (300mg, 1.36mmol), 5, 6-dimethylpyridin-2-amine (249mg, 2.04mmol) in acetonitrile (8mL) and the mixture was heated in an oil bath at 140 ℃ for 18 h. After cooling to room temperature, the mixture was concentrated in vacuo, adsorbed onto silica gel and then purified by chromatography (silica gel, 50 μm, 80g column, from Analogix, 0% -10% acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxylate (150mg, 36%) as a yellow solid.¹H NMR(400MHz,DMSO-d₆)ppm10.20(s,1H)8.86(s,1H)7.57(d,J＝8.08Hz,1H)6.97(d,J＝8.08Hz,1H)4.40(q,J＝7.24Hz,2H)2.42(s,3H)2.23(s,3H)1.35(t,J＝7.20Hz,3H)；LCMS(EI/CI)m/z:307[M+H].

Step 2

6-chloro-4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide

To a pressure tube were added ethyl 6-chloro-4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxylate (133mg, 434. mu. mol) and a solution of 7N ammonia in methanol (9.44g, 12mL, 84.0 mmol). The mixture was heated in an oil bath at 50 ℃ for 18 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo to give 6-chloro-4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide (160mg, 100%) as a yellow solid.¹H NMR (400MHz, chloroform-d) ppm11.48(br.s.,1H)9.18(s,1H)8.17(br.s.,1H)7.43(d, J ═ 8.34Hz,1H)6.74(d, J ═ 7.83Hz,1H)5.67(br.s.,1H)2.53(s,3H)2.28(s, 3H); LCMS (EI/CI) M/z:278[ M + H]. This material was used in the next step without further purification.

Step 3

6- ((3R,4R) -3-Aminotetrahydro-2H-pyran-4-ylamino) -4- (5, 6-dimethylpyridin-2-ylamino) pyridazin Oxazine-3-carboxamides

A solution of 6-chloro-4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide (120mg, 432. mu. mol) and tert-butyl (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamate (187mg, 864. mu. mol) in N-methyl-2-pyrrolidone (6mL) was heated at 150 ℃ for 1.5 days. After evaporation of the solvent, the residue was dissolved in dichloromethane (2mL) and TFA (370mg, 250. mu.L, 3.24 mmol). The mixture was stirred at room temperature for 3 hours, then the solvent was evaporated and purified by chromatography (spherical silica gel, 20-45 μm, 11g, Versaflash from Supelco, 97:2.75:0.15-87:12.35:0.65 dichloromethane: MeOH: NH)₄OH, 20 min) to afford a brown solid. The brown solid was dissolved in dichloromethane and 10mL cyclohexane was added. After standing, a solid precipitate formed. The supernatant was decanted and the solid residue was dried under vacuum to give 6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide (18mg, 12% over two steps) as a brown solid.¹H NMR (400MHz, chloroform-d) ppm11.23(br.s.,1H)8.29(s,1H)8.03(br.s.,1H)7.36(d, J ═ 8.08Hz,1H)6.67(d, J ═ 8.08Hz,1H)5.68-5.79(m,1H)5.39(br.s.,1H)4.02(d, J ═ 7.33Hz,1H)3.88(d, J ═ 11.12Hz,1H)3.69(d, J ═ 11.62Hz,1H)3.55(t, J ═ 11.49Hz,1H)3.10(br.s.,1H)2.49(s,3H)2.25(s,3H)2.02(d, J ═ 12H), 1H ═ 1H (1H) 3.84 (H, 1H) 3.42H); LCMS (EI/CI) M/z:358[ M + H ]].

Example 9

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (1-methyl-1H-pyrazol-3-ylamino) -pyridazine-3-carboxamide

Step 1

6-chloro-4- (1-methyl-1H-pyrazol-3-ylamino) -pyridazine-3-carboxylic acid methyl ester

Methyl 4, 6-dichloro-pyridazine-3-carboxylate (165mg, 0.8mmol) and 1-methyl-1H-pyrazol-3-amine (81mg, 0.837mmol) were dissolved in N-methylpyrrolidone (3.2 mL). The reaction was heated at 110 ℃ for 2 hours, then cooled and concentrated in vacuo. The residue was diluted with water and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica gel, 10-70% ethyl acetate in hexanes) afforded methyl 6-chloro-4- (1-methyl-1H-pyrazol-3-ylamino) -pyridazine-3-carboxylate (69mg, 32%) as a light brown solid.¹HNMR (300MHz, chloroform-d) ppm10.09(br.s.,1H)8.24(s,1H)7.34(d, J ═ 2.3Hz,1H)6.02(d, J ═ 2.3Hz,1H)4.08(s,3H)3.91(s, 3H); LCMS (EI/CI) M/z 268[ M + H].

Step 2

6-chloro-4- (1-methyl-1H-pyrazol-3-ylamino) -pyridazine-3-carboxamide

Methyl 6-chloro-4- (1-methyl-1H-pyrazol-3-ylamino) -pyridazine-3-carboxylate (75mg, 0.28mmol) was suspended in a solution of 7M ammonia in methanol (3 mL). After 16H, the reaction mixture was concentrated in vacuo to give 6-chloro-4- (1-methyl-1H-pyrazol-3-ylamino) -pyridazine-3-carboxamide (70mg, 100%) as an off-white solid, which was used in the next step without purification.¹H NMR(300MHz,DMSO-d₆)ppm11.39(s,1H)8.77(br.s.,1H)8.24(s,1H)8.13(br.s.,1H)7.72(d,J＝2.3Hz,1H)6.18(d,J＝2.3Hz,1H)3.84(s,3H)；LCMS(EI/CI)m/z:253[M+H].

Step 3

{ (1S,2R) -2- [ 6-carbamoyl-5- (1-methyl-1H-pyrazol-3-ylamino) -pyridazin-3-ylamino]-Ring Hexyl } -carbamic acid tert-butyl ester

6-chloro-4- (1-methyl-1H-pyrazol-3-ylamino) -pyridazine-3-carboxamide (60mg, 0.237mmol) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (102mg, 0.475mmol) were dissolved in N-methylpyrrolidone (1.5 mL). The reaction mixture was heated at 150 ℃ for 16 hours, then additional tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (100mg total, 0.47mmol) was added in three portions over 6 days. The reaction mixture was cooled, diluted with ethyl acetate and water, and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, then dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0-7% methanol in dichloromethane) to give { (1S,2R) -2- [ 6-carbamoyl-5- (1-methyl-1H-pyrazol-3-ylamino) -pyridazin-3-ylamino]-cyclohexyl } -carbamic acid tert-butyl ester (18mg, 17%) as brown amorphous residue.¹H NMR (300MHz, chloroform-d) ppm10.68-10.80(m,1H)7.89-8.06(m,1H)7.34-7.37(m,1H)7.25(d, J ═ 2.3Hz,1H)5.93(d, J ═ 2.3Hz,1H)5.56-5.64(m,1H)5.02-5.14(m,1H)3.91-4.01(m,1H)3.86(s,3H)1.55(br.s.,8H)1.40(s, 9H); LCMS (EI/CI) M/z:431[ M + H].

Step 4

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (1-methyl-1H-pyrazol-3-ylamino) -pyridazine-3-carboxylic acid Amines as pesticides

Reacting { (1S,2R) -2- [ 6-carbamoyl-5- (1-methyl-1H-pyrazol-3-ylamino) -pyridazin-3-ylamino]-cyclohexyl } -carbamic acid tert-butyl ester (34mg, 0.079mmol) was dissolved in dichloromethane (1mL) and then cooled to 0 ℃. Trifluoroacetic acid (0.5mL, 6.49mmol) was added dropwise and the reaction mixture was then warmed to 25 ℃. After 4 hours, the mixture was cooled in an ice bath and neutralized with sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. By chromatography (silica gel, 0-80% 0.1:0.01 methanol: NH)₄A solution of OH in dichloromethane) to give 6- ((1R,2S) -2-amino-cyclohexylamino) -4- (1-methyl-1H-pyrazol-3-ylamino) -pyridazine-3-carboxamide (5mg, 20%) as a brown solid.¹H NMR(300MHz,DMSO-d₆)ppm10.84-10.89(m,1H)8.23-8.32(m,1H)7.66(d,J＝2.3Hz,1H)7.48-7.59(m,1H)7.10(s,1H)6.73(d,J＝7.9Hz,1H)6.05(d,J＝2.3Hz,1H)3.91-4.05(m,1H)3.01-3.11(m,1H)1.46-1.72(m,6H)1.25-1.36(m,2H)；LCMS(EI/CI)m/z:331[M+H].

Example 10

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide

Step 1

6-chloro-4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxylic acid ethyl ester

4, 6-dichloro-pyridazine-3-carboxylic acid ethyl ester (300mg, 1.36mmol) and 6-methylpyridin-2-amine (176mg, 1.63mmol) were dissolved in acetonitrile (4.1mL) and then heated at 140 ℃ for 16 hours. A second portion of 6-methylpyridin-2-amine (73mg, 0.67mmol) was added. After an additional 2 days at 140 ℃, the reaction mixture was cooled and concentrated in vacuo. Purification by chromatography (silica gel, 5-40% ethyl acetate in hexanes) gave ethyl 6-chloro-4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxylate (146mg, 36%) as a light yellow oil.¹H NMR (300MHz, chloroform-d) ppm10.68(br.s.,1H)9.21(s,1H)7.59(t, J ═ 7.7Hz,1H)6.90(d, J ═ 7.6Hz,1H)6.76(d, J ═ 7.9Hz,1H)4.57(q, J ═ 7.2Hz,2H)2.57(s,3H)1.51(t, J ═ 7.0Hz, 3H); LCMS (EI/CI) m/z:315

[M+Na].

Step 2

6-chloro-4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide

Ethyl 6-chloro-4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxylate (137mg, 0.468mmol) was suspended in a solution of 7M ammonia in methanol (3 mL). After 4h, the reaction mixture was concentrated in vacuo to give 6-chloro-4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide (123mg, 100%) as an off-white solid, which was used in the next step without purification. LCMS (EI/CI) M/z:264[ M + H ].

Step 3

{ (1S,2R) -2- [ 6-carbamoyl-5- (6-methyl-pyridin-2-ylamino) -pyridazin-3-ylamino]-Cyclohexan-cyclohexane Methyl-carbamic acid tert-butyl ester

6-chloro-4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide (130mg, 0.49mmol), N-diisopropylethylamine (0.17mL, 0.986mmol) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (211mg, 0.986mmol) were dissolved in N-methylpyrrolidone (2mL) and heated at 150 ℃ for 2 days. The reaction mixture was cooled and concentrated in vacuo, then diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica gel, 0-5% methanol in dichloromethane) gave { (1S,2R) -2- [ 6-carbamoyl-5- (6-methyl-pyridin-2-ylamino) -pyridazin-3-ylamino ] -cyclohexyl } -carbamic acid tert-butyl ester (78mg, 35%) as a light brown amorphous residue. LCMS (EI/CI) M/z:442[ M + H ].

Step 4

Reacting { (1S,2R) -2- [ 6-carbamoyl-5- (6-methyl-pyridin-2-ylamino) -pyridazin-3-ylamino]-cyclohexyl } -carbamic acid tert-butyl ester (188mg, 0.426mmol) was dissolved in dichloromethane (4mL) and then cooled to 0 ℃. Trifluoroacetic acid (2mL, 25mmol) was added dropwise and the reaction mixture was then warmed to 25 ℃. After 4 hours, the mixture was cooled in an ice bath and neutralized with sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. By chromatography (silica gel, 0-100% 0.1:0.01 methanol: NH)₄Solution of OH in dichloromethane) to obtain 6- ((1R,2S) -2-amino-cyclohexylamino) -4- (6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide (61mg, 42%) as a light brown solid.¹H NMR(400MHz,DMSO-d₆)ppm11.61(s,1H)8.35-8.44(m,1H)8.10(s,1H)7.61(br.s,1H)7.61(t,J＝7.3Hz,1H)6.81-6.89(m,1H)6.85(d,J＝7.3Hz,1H)6.76(d,J＝8.1Hz,1H)3.76-3.99(m,2H)3.11-3.18(m,1H)2.48-2.49(m,3H)1.49-1.77(m,7H)1.27-1.38(m,2H)；LCMS(EI/CI)m/z:342[M+H].

Example 11

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-ylamino) -pyridazine-3-carboxamide

Step 1

(3-methyl-pyridin-2-yl) -carbamic acid tert-butyl ester

3-methylpyridin-2-amine (20g, 185mmol) was dissolved in ethyl acetate (30mL) and added dropwise to a solution of di-tert-butyl carbonate (64.6g, 296mmol) in hexane (72mL) at 60 ℃. After 3 hours, the mixture was cooled to 25 ℃. After 16 hours, hexane (70mL) was added. After 2 hours, the solid precipitate was filtered, the filter cake was rinsed with hexane and then dried to give (3-methyl-pyridin-2-yl) -carbamic acid tert-butyl ester (27.4g, 71%) as a white solid.¹H NMR (400MHz, chloroform-d) ppm8.24-8.29(m,1H)7.49-7.54(m,1H)7.00-7.07(m,1H)2.30(s,3H)1.52(s, 9H); LCMS (EI/CI) M/z:209[ M + H].

Step 2

1H-pyrrolo [2,3-b]Pyridine compound

(3-methyl-pyridin-2-yl) -carbamic acid tert-butyl ester (5g, 24mmol) was dissolved in tetrahydrofuran (96mL) and cooled to-15 ℃ in an ice-salt bath. Butyl lithium solution (1.6M in hexanes, 30mL, 48mmol) was added over 30 minutes. Is 1 times smallerAfter this time, N-dimethylformamide (1.9mL, 34.5mmol) was added and the reaction mixture was warmed to 25 ℃ for 16 hours. The reaction mixture was slowly added to about 150mL6M HCl solution. The resulting mixture was warmed to 55 ℃ for 2 hours, then cooled, the layers separated, and ethyl acetate was added to the aqueous layer. 6M sodium hydroxide solution was slowly added until pH6, then the layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined ethyl acetate extracts were washed with sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo to give 1H-pyrrolo [2,3-b ] in]Pyridine (3.8g, 134%) as a brown semisolid. It was used in the next step without further purification.¹H NMR (300MHz, chloroform-d) ppm10.86(br.s.,1H)8.28(dd, J ═ 4.9,1.5Hz,1H)7.98(dd, J ═ 7.7,1.7Hz,1H)7.36(d, J ═ 3.4Hz,1H)7.10(dd, J ═ 7.9,4.9Hz,1H)6.51(d, J ═ 3.4Hz, 1H); LCMS (EI/CI) M/z:119[ M + H].

Step 3

1H-pyrrolo [2,3-b]Pyridine 7-oxide, 3-chlorobenzoic acid complex

1H-pyrrolo [2,3-b ] pyridine (2.8g, 24mmol) was dissolved in ethyl acetate (24mL) and cooled to 0 ℃. A solution of 3-chloroperbenzoic acid (77%, 6.7g, 30.1mmol) in ethyl acetate (24mL) was added dropwise, and the reaction mixture was warmed to 25 ℃ for 16 hours. The reaction mixture was cooled to 0 ℃, filtered, and the solid was dried to give crude 1H-pyrrolo [2,3-b ] pyridine 7-oxide, 3-chlorobenzoic acid complex (4.1g, 58%) as an off-white solid. It was used in the next step without purification. LCMS (EI/CI) M/z:135[ M + H ].

Step 4

1H-pyrrolo [2,3-b]Pyridin-6-ylamines

1H-pyrrolo [2,3-b ]]Pyridine 7-oxide, 3-chlorobenzoic acid complex (1.5g, 5.16mmol) was suspended in acetonitrile (10 mL). Dimethyl sulfate (0.54mL, 5.68mmol) was added and the reaction mixture was warmed to 60 ℃. After 16 hours, the mixture was transferred to a thick-walled pressure tube and 7M ammonia in methanol (11mL) was added. Seal and warm the tube to 55 ℃ is adopted. After 16 hours, the solvent was evaporated and the residue was dissolved in dichloromethane and 10% sodium carbonate solution. The aqueous layer was extracted with dichloromethane and the combined organic layers were then washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic phase was dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica gel, 10-80% ethyl acetate in hexane) afforded 1H-pyrrolo [2, 3-b%]Pyridin-6-ylamine (316mg, 46%) as a white solid.¹H NMR (400MHz, chloroform-d) ppm8.73(br.s.,1H)7.70(d, J ═ 8.3Hz,1H)6.99(d, J ═ 3.5Hz,1H)6.38(d, J ═ 8.3Hz,1H)6.36(d, J ═ 3.5Hz,1H)3.82(br.s.,2H).

Step 5

2- (1H-pyrrolo [2, 3-b)]Pyridin-6-yl) -isoindole-1, 3-dione

1H-pyrrolo [2,3-b ]]Pyridin-6-ylamine (0.12g, 0.9mmol) was suspended in acetic acid (1.5mL), then phthalic anhydride (133mg, 0.9mmol) and sodium acetate (118mg, 1.44mmol) were added and the mixture was heated to 120 ℃. After 3 hours, the mixture was concentrated in vacuo and the residue obtained was dissolved in ethyl acetate and then cooled to 0 ℃. Ice water and sodium bicarbonate solution were added, and then the aqueous layer was extracted with ethyl acetate. The aqueous layer was adjusted to pH6 with 1M HCl solution and extracted twice more with ethyl acetate. The combined organic layers were dried over sodium sulfate and then concentrated in vacuo. Purification by chromatography (silica gel, 20-70% ethyl acetate in hexane) afforded 2- (1H-pyrrolo [2, 3-b)]Pyridin-6-yl) -isoindole-1, 3-dione (179mg, 75%) as a light brown solid.¹H NMR(300MHz,DMSO-d₆)ppm11.91(br.s.,1H)8.15(d,J＝7.9Hz,1H)7.90-8.05(m,4H)7.59-7.65(m,1H)7.21(d,J＝7.9Hz,1H)6.54-6.60(m,1H)；LCMS(EI/CI)m/z:264[M+H].

Step 6

2- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) -isoindole-1, 3-dione

2- (1H-pyrrolo [2,3-b ] pyridin-6-yl) -isoindole-1, 3-dione (179mg, 0.68mmol) was suspended in acetonitrile (3.4 mL). Methyl iodide (53 μ L, 0.843mmol) and cesium carbonate (443mg, 1.36mmol) were then added. After 16h, water was added and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate), filtered and concentrated in vacuo to give 2- (1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -isoindole-1, 3-dione (0.22g, 117%) as a light brown solid, which was used in the next step without purification. LCMS (EI/CI) M/z:278[ M + H ].

Step 7

1-methyl-1H-pyrrolo [2,3-b]Pyridin-6-ylamines

2- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) -isoindole-1, 3-dione (220mg, 0.793mmol) was dissolved in ethanol (4mL) and hydrazine (0.5mL, 15.9mmol) was added. After 16h, the mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous layer was extracted two more times with ethyl acetate, then the combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica gel, 10-50% ethyl acetate in hexane) afforded 1-methyl-1H-pyrrolo [2,3-b ]]Pyridin-6-ylamine (115mg, 98%) as an off-white solid.¹H NMR (300MHz, chloroform-d) ppm7.67(d, J ═ 8.3Hz,1H)6.87(d, J ═ 3.4Hz,1H)6.35(d, J ═ 8.3Hz,1H)6.30(d, J ═ 3.4Hz,1H)4.38(br.s.,2H)3.76(s, 3H); LCMS (EI/CI) M/z:148[ M + H].

Step 8

6-chloro-4- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-ylamino) -pyridazine-3-carboxylic acid ethyl ester

4, 6-dichloro-pyridazine-3-carboxylic acid ethyl ester (195mg, 0.882mmol) and 1-methyl-1H-pyrrolo [2,3-b ]]Pyridin-6-ylamine (156mg, 1.06mmol) was dissolved in acetonitrile (2.7mL) and then heated at 140 ℃ for 2 days. The reaction mixture was cooled and concentrated in vacuo. The residue was diluted with water and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica gel, 5-70% ethyl acetate in hexane) afforded 6-chloro-4- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-ylamino) -pyridazin-3Ethyl formate (52mg, 18%) as a pale yellow solid.¹H NMR (400MHz, chloroform-d) ppm10.78(s,1H)9.34(s,1H)7.90(d, J ═ 8.3Hz,1H)7.14(d, J ═ 3.3Hz,1H)6.74(d, J ═ 8.3Hz,1H)6.45(d, J ═ 3.5Hz,1H)4.58(d, J ═ 7.1Hz,2H)3.90(s,3H)1.52(t, J ═ 7.2Hz, 3H); LCMS (EI/CI) M/z:332[ M + H].

Step 9

6-chloro-4- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-ylamino) -pyridazine-3-carboxamides

Reacting 6-chloro-4- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-ylamino) -pyridazine-3-carboxylic acid ethyl ester (52mg, 0.157mmol) was suspended in 7M ammonia in methanol (2 mL). After 2 hours, the reaction mixture was concentrated in vacuo to give 6-chloro-4- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-ylamino) -pyridazine-3-carboxamide (47mg, 100%) was used in the next step without purification as a pale yellow solid.¹H NMR(400MHz,DMSO-d₆)ppm12.07(s,1H)9.24(s,1H)8.85(br.s.,1H)8.21(br.s.,1H)7.99(d,J＝8.3Hz,1H)7.42(d,J＝3.3Hz,1H)6.81(d,J＝8.3Hz,1H)6.45(d,J＝3.3Hz,1H)3.83(s,3H)；LCMS(EI/CI)m/z:303[M+H].

Step 10

{ (1S,2R) -2- [ 6-carbamoyl-5- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-ylamino) -pyridazine- 3-ylamino group]-cyclohexyl } -carbamic acid tert-butyl ester

6-chloro-4- (1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-ylamino) -pyridazine-3-carboxamide (42mg, 0.139mmol) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (89mg, 0.416mmol) were dissolved in N-methylpyrrolidone (1.4mL) and heated at 150 ℃ for 36 hours. Additional tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (35mg, 0.16mmol) was added and heating continued for an additional 16 hours. The reaction mixture was cooled and concentrated in vacuo, then diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica gel, 0-5% methanol in dichloromethane) gave { (1S,2R) -2- [ 6-carbamoyl-5- (1-methyl-1H-pyrrolo [2,3-b ] pyridin-6-ylamino) -pyridazin-3-ylamino ] -cyclohexyl } -carbamic acid tert-butyl ester (12mg, 18%) as a light brown amorphous residue. LCMS (EI/CI) M/z:481[ M + H ].

Step 11

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-ylamino Yl) -pyridazine-3-carboxamides

Reacting { (1S,2R) -2- [ 6-carbamoyl-5- (1-methyl-1H-pyrrolo [2,3-b ]]Pyridin-6-ylamino) -pyridazin-3-ylamino]-cyclohexyl } -carbamic acid tert-butyl ester (23mg, 0.048mmol) was dissolved in dichloromethane (1mL) and then cooled to 0 ℃. Trifluoroacetic acid (0.5mL, 6.5mmol) was added dropwise and the reaction mixture was then warmed to 25 ℃. After 2 hours, the mixture was cooled in an ice bath and neutralized with sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. By chromatography (silica gel, 0-100% 0.1:0.01 methanol: NH)₄Solution of OH in dichloromethane) to give 6- ((1R,2S) -2-amino-cyclohexylamino) -4- (1-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-ylamino) -pyridazine-3-carboxamide (5.8mg, 32%) was a light brown solid.¹H NMR(400MHz,DMSO-d₆)ppm11.74-11.82(m,1H)8.35-8.44(m,1H)8.14(s,1H)7.90(d,J＝8.3Hz,1H)7.60-7.67(m,1H)7.32(d,J＝3.3Hz,1H)6.80(d,J＝7.6Hz,1H)6.66(d,J＝8.3Hz,1H)6.40(d,J＝3.3Hz,1H)3.86(s,3H)3.11-3.17(m,1H)1.50-1.75(m,8H)1.23-1.36(m,3H)；LCMS(EI/CI)m/z:381[M+H].

Example 12

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

6-chloro-4- (6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

Ethyl 4, 6-dichloropyridazine-3-carboxylate (300mg, 1.36mmol), 6-cyclopropylpyridin-2-amine (273mg, 2.04mmol) and acetonitrile (8mL) were added to a pressure tube and heated at 140 ℃ for 20 hours. After cooling to room temperature, the mixture was concentrated in vacuo and the obtained residue was purified by chromatography (silica gel, 50 μm, 80g, Analogix, 0-10% acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4- (6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxylate (145mg, 34%) as a yellow solid.¹H NMR (400MHz, chloroform-d) ppm10.64(br.s.,1H)9.39(s,1H)7.63(t, J ═ 7.83Hz,1H)6.94(d, J ═ 7.58Hz,1H)6.78(d, J ═ 8.08Hz,1H)4.12(s,3H) 1.99-2.10(M,1H)1.06-1.12(M,4H). LCMS (EI/CI) M/z 319[ M + H) M/z].

Step 2

6-chloro-4- (6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide

Ethyl 6-chloro-4- (6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxylate (140mg, 439. mu. mol) and ammonia (7M in methanol, 9.44g, 12mL, 84.0mmol) were heated at 50 ℃ for 21 h in a sealed tube. After cooling to room temperature, concentration in vacuo afforded 6-chloro-4- (6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide (112mg, 88%) as a yellow solid.¹H NMR (300MHz, chloroform-d) ppm11.51(br.s.,1H)9.16(s,1H)8.16(br.s.,1H)7.52(t, J ═ 7.74Hz,1H)6.86-6.96(M,1H)6.68(d, J ═ 7.93Hz,1H)5.65(br.s.,1H)1.99-2.10(M,1H)1.06-1.12(M,4H) LCMS (EI/CI) M/z 290[ M + H ] M/CI]The crude product was used in the next step without further purification.

Step 3

(1S,2R) -2- (6-carbamoyl-5- (6-cyclopropylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylamino Benzoic acid tert-butyl ester

To a stirred solution of 6-chloro-4- (6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide (104mg, 359. mu. mol) in N-methyl-2-pyrrolidone (5mL) were added DMAP (47mg, 377. mu. mol) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (154mg, 718. mu. mol). The mixture was heated to 150 ℃ for 1.5 days, then N was added₂A stream was blown into the flask while heating at 140 ℃ to evaporate the volatile solvent. The residue obtained is purified by chromatography (silica gel, 50 μm, 60g, Analogix, 97:2.75:0.15-84:15.2:0.8 dichloromethane: MeOH: NH)₄OH, 30 min) to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (6-cyclopropylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (126mg, containing some residual NMP) as a brown viscous oil.¹H NMR (300MHz, chloroform-d) ppm11.43(br.s.,1H)8.17(br.s.,1H)8.03(br.s.,1H)7.44(br.s.,1H)7.03(br.s.,1H)6.80(br.s.,1H)6.60(br.s.,1H)5.76(br.s.,1H)5.49(br.s.,1H)3.82(br.s.,1H)3.24(br.s.,1H)2.03(br.s.,1H)1.32-1.91(M,8H)1.45(s.,9H)1.05(d, J ═ 16.62Hz,4H) s (CI/z) M + m.m.m.l.m.m.m.m., 9H) 468H [ l.s., "m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m.m]It was used directly in the next step without further purification.

Step 4

To a solution of tert-butyl (1S,2R) -2- (6-carbamoyl-5- (6-cyclopropylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (25mg, 53.5. mu. mol) in dichloromethane (4mL) was added TFA (370. mu.g, 0.25. mu.L, 3.24. mu. mol). After 6h, the mixture was concentrated in vacuo and then purified by flash chromatography (spherical silica gel, 20-45 μm, 25g, Versaflash, ex Supelco, 97:2.75: 0.15)-84:15.2:0.8 dichloromethane: MeOH: NH₄OH, 30 min) to afford 6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide (13mg, 10%, two steps) as a brown solid.¹H NMR (300MHz, chloroform-d) ppm11.43(br.s.,1H)8.17(br.s.,1H)8.03(br.s.,1H)7.44(br.s.,1H)7.03(br.s.,1H)6.80(br.s.,1H)6.60(br.s.,1H)5.76(br.s.,1H)5.49(br.s.,1H)3.82(br.s.,1H)3.24(br.s.,1H)2.03 (lcm.s., 1H)1.32-1.91(M,8H)1.05(d, J ═ 16.62Hz, EI 4H) s (CI/H) M/z 368[ M + H ] M/z].

Example 13

6- ((1R,2S) -2-aminocyclohexylamino) -4- (5-fluoro-6-methylpyridin-2-ylaminopyridazine-3-carboxamide

Step 1

6-chloro-4- (5-fluoro-6-methylpyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

To the pressure tube were added ethyl 4, 6-dichloropyridazine-3-carboxylate (300mg, 1.36mmol), 5-fluoro-6-methylpyridin-2-amine (257mg, 2.04mmol) and acetonitrile (8mL), followed by heating at 140 ℃ for 3 days. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by chromatography (silica gel, 50 μm, 80g, Analogix, 0-10% acetone in dichloromethane, 25 min) to give ethyl 6-chloro-4- (5-fluoro-6-methylpyridin-2-ylamino) pyridazine-3-carboxylate (69mg, 16%) as a yellow solid.¹HNMR (400MHz, chloroform-d) ppm10.72(br.s.,1H)9.06(s,1H)7.38(s,1H)6.74-6.85(M,1H)4.58(q, J ═ 7.07Hz,2H)2.56(d, J ═ 3.03Hz,3H)1.53(t, J ═ 7.07Hz,3H)1.27(s,1H). LCMS (EI/CI) M/z 311[ M + H, 1H ]: 311].

Step 2

6-chloro-4- (5-fluoro-6-methylpyridin-2-ylamino) pyridazine-3-carboxamide

To a pressure tube containing 7M ammonia in methanol (9.44g, 12mL, 84.0mmol) was added ethyl 6-chloro-4- (5-fluoro-6-methylpyridin-2-ylamino) pyridazine-3-carboxylate (111.2mg, 358. mu. mol). The reaction mixture was heated to 50 ℃ for 6 hours, then concentrated in vacuo to give 6-chloro-4- (5-fluoro-6-methylpyridin-2-ylamino) pyridazine-3-carboxamide (110mg 100%) as a yellow solid.¹H NMR (300MHz, chloroform-d) ppm11.67(br.s.,1H)9.10(s,1H)8.17(br.s.,1H)7.35(t, J ═ 8.50Hz,1H)6.79(dd, J ═ 8.69,3.02Hz,1H)5.67(br.s.,1H)2.54(d, J ═ 3.02Hz,3H) LCMS (EI/CI) M/z 282[ M + H]The crude product was used in the next step without further purification.

Step 3

(1S,2R) -2- (6-carbamoyl-5- (5-fluoro-6-methylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexan-e Carbamic acid tert-butyl ester

To a solution of 6-chloro-4- (5-fluoro-6-methylpyridin-2-ylamino) pyridazine-3-carboxamide (109mg, 387 μmol) in N-methyl-2-pyrrolidone (2.4mL) were added DMAP (50.7mg, 406 μmol) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (166mg, 774 μmol), and the mixture was heated to 150 ℃ for 1.5 days. Will N₂The mixture was blown in while still heating at 140 ℃ to evaporate NMP, then chromatographed (silica gel, 50 μm, 40g, Analogix, 97:2.75:0.15-84:15.2:0.8 dichloromethane: MeOH: NH)₄OH, 30 min) to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (5-fluoro-6-methylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (82mg, 23%) as a brown oil.¹H NMR (400MHz, chloroform-d) ppm11.43(s,1H)8.24(s,1H)8.08(br.s.,2H)7.22-7.37(m,1H)6.66-6.77(m,1H)5.64 (d),J＝3.28Hz,1H)4.02(br.s.,2H)2.49(d,J＝3.03Hz,3H)1.67-1.92(m,2H)1.35-1.65(m,8H).LCMS(EI/CI)m/z:460[M+H].

Step 4

To a solution of tert-butyl (1S,2R) -2- (6-carbamoyl-5- (5-fluoro-6-methylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (40mg, 87.0. mu. mol) in dichloromethane (3.2mL) was added TFA (592. mu.g, 0.400. mu.L, 5.19. mu. mol), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and then chromatographed (spherical silica gel, 20-45 μm,23 g, Versaflash, from Supelco, 99:0.95:0.05-90:9.5:0.5 dichloromethane: MeOH: NH)₄OH, 25 min) to afford 6- ((1R,2S) -2-aminocyclohexylamino) -4- (5-fluoro-6-methylpyridin-2-ylaminopyridazine-3-carboxamide (10mg, 32% yield) as a light brown solid.¹H NMR(400MHz,DMSO-d₆)ppm11.65(s,1H)8.38(br.s.,1H)7.97(s,1H)7.54-7.69(m,2H)6.75-6.94(m,2H)3.15(d,J＝3.03Hz,1H)2.47(d,J＝2.78Hz,3H)1.44-1.84(m,8H)1.33(br.s.,2H).LCMS(EI/CI)m/z:360[M+H].

Example 14

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (6-ethyl-pyridin-2-ylamino) -pyridazine-3-carboxamide

Step 1

6-chloro-4- (6-ethyl-pyridin-2-ylamino) -pyridazine-3-carboxylic acid ethyl ester

4, 6-dichloro-pyridazine-3-carboxylic acid ethyl ester (500mg, 2.26mmol) and 6-ethylpyridin-2-amine (415mg, 3.39mmol) were dissolved in acetonitrile (7mL) and then heated at 140 ℃ for 3 days. The reaction mixture was cooled and concentrated in vacuo. Purification by chromatography (silica gel, 5-50% ethyl acetate in hexanes) afforded ethyl 6-chloro-4- (6-ethyl-pyridin-2-ylamino) -pyridazine-3-carboxylate (246mg, 35%%) as a light brown solid.¹H NMR (400MHz, chloroform-d) ppm10.68(br.s.,1H)9.30(s,1H)7.61(t, J ═ 7.8Hz,1H)6.91(d, J ═ 7.3Hz,1H)6.77(d, J ═ 7.8Hz,1H)4.57(q, J ═ 7.2Hz,2H)2.86(q, J ═ 7.6Hz,2H)1.52(t, J ═ 7.1Hz,3H)1.38(t, J ═ 7.5Hz, 3H); LCMS (EI/CI) M/z:307[ M + H].

Step 2

6-chloro-4- (6-ethyl-pyridin-2-ylamino) -pyridazine-3-carboxamide

Ethyl 6-chloro-4- (6-ethyl-pyridin-2-ylamino) -pyridazine-3-carboxylate (241mg, 0.786mmol) was suspended in 7M ammonia in methanol (9 mL). After 3h, the reaction mixture was concentrated in vacuo to give 6-chloro-4- (6-ethyl-pyridin-2-ylamino) -pyridazine-3-carboxamide (218mg, 100%) as an off-white solid, which was used in the next step without purification. LCMS (EI/CI) M/z:278[ M + H ].

Step 3

{ (1S,2R) -2- [ 6-carbamoyl-5- (6-ethyl-pyridin-2-ylamino) -pyridazin-3-ylamino]-Cyclohexan-cyclohexane Methyl-carbamic acid tert-butyl ester

6-chloro-4- (6-ethyl-pyridin-2-ylamino) -pyridazine-3-carboxamide (218mg, 0.785mmol) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (336mg, 1.57mmol) were dissolved in N-methylpyrrolidone (4mL) and heated at 150 ℃ for 40 hours. Additional tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (168mg, 0.78mmol) was added and heating continued for an additional 16 hours. The reaction mixture was cooled and concentrated in vacuo, then diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. By chromatography (on silica gel, 0-5% methanol)Dichloromethane solution) to obtain { (1S,2R) -2- [ 6-carbamoyl-5- (6-ethyl-pyridin-2-ylamino) -pyridazin-3-ylamino]-cyclohexyl } -carbamic acid tert-butyl ester (167mg, 46%) as a light brown amorphous residue.¹HNMR (300MHz, chloroform-d) ppm11.44(s,1H)8.47(s,1H)7.97-8.03(m,1H)7.52(t, J ═ 7.6Hz,1H)7.22-7.26(m,1H)6.78(d, J ═ 7.2Hz,1H)6.70(d, J ═ 7.9Hz,1H)5.38-5.43(m,1H)4.92-5.00(m,1H)3.97-4.08(m,2H)2.80(q, J ═ 7.6Hz,2H)1.58-1.96(m,8H)1.41(s,9H)1.31-1.39(m, 3H); LCMS (EI/CI) M/z:456[ M + H ]].

Step 4

Reacting { (1S,2R) -2- [ 6-carbamoyl-5- (6-ethyl-pyridin-2-ylamino) -pyridazin-3-ylamino]-cyclohexyl } -carbamic acid tert-butyl ester (167mg, 0.367mmol) was dissolved in dichloromethane (4mL) and then cooled to 0 ℃. Trifluoroacetic acid (2mL, 26mmol) was added dropwise and the reaction mixture was then warmed to 25 ℃. After 5 hours, the mixture was cooled in an ice bath and neutralized with sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. By chromatography (silica gel, 5-80% 0.1:0.01 methanol: NH)₄A solution of OH in dichloromethane) to give 6- ((1R,2S) -2-amino-cyclohexylamino) -4- (6-ethyl-pyridin-2-ylamino) -pyridazine-3-carboxamide (66mg, 50%) as a light brown solid.¹H NMR(400MHz,DMSO-d₆)ppm11.66(s,1H)8.35-8.40(m,1H)8.09(s,1H)7.63(dd,J＝8.2,7.5Hz,1H)7.62(br.s.,1H)6.86(d,J＝7.6Hz,1H)6.79(d,J＝7.6Hz,1H)6.76(d,J＝7.8Hz,1H)3.73-3.86(m,1H)3.10-3.15(m,1H)2.75(q,J＝7.6Hz,2H)1.48-1.73(m,7H)1.27(t,J＝7.7Hz,3H)1.24-1.37(m,2H)；LCMS(EI/CI)m/z:356[M+H].

Example 15

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (5, 6-dimethyl-pyridin-2-ylamino) -pyridazine-3-carboxamide

Step 1

To a thick-walled sealable tube was added ethyl 4, 6-dichloropyridazine-3-carboxylate (300mg, 1.36mmol) and 5, 6-dimethylpyridin-2-amine (249mg, 2.04 mmol). To this mixture was added acetonitrile (8.00mL) and the reaction mixture was heated with stirring in an oil bath at 140 ℃ for 20 hours. After cooling to room temperature, the residue was suspended in dichloromethane and purified by flash chromatography (silica gel, 20-45 μ M, 40g, Thomson) eluting with 0-10% acetone/dichloromethane for 20 min to give ethyl 6-chloro-4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxylate (195mg, 46.8%) as an off-white solid.¹H NMR (chloroform-d) 10.54(s,1H),9.14(s,1H),7.41(d, J ═ 8.3Hz,1H),6.70(d, J ═ 8.3Hz,1H),4.55(q, J ═ 7.2Hz,2H),2.50(s,3H),2.26(s,3H),1.50(t, J ═ 7.2Hz, 3H); LC-MS307.0[ M + H ]]⁺.

Step 2

6-chloro-4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide

In a 50mL round-bottom flask, ethyl 6-chloro-4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxylate (929mg, 3.03mmol) was suspended in a solution of 7M ammonia in methanol (7.87g, 10.0mL, 70.0 mmol). The flask was sealed and stirred at room temperature for 2 hours. The solvent was evaporated and the solid residue dried under high vacuum to give 6-chloro-4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide (841mg, 100% yield) as an off-white solid.¹H NMR (chloroform-d) 11.37(br.s.,1H),9.11(s,1H),8.09(br.s.,1H),7.32(d, J ═ 8.3Hz,1H),6.63(d, J ═ 8.1Hz,1H),5.59 (c: (c, J ═ 8.1Hz,1H), and (c, d, cbr.s.,1H),2.43(s,3H),2.19(s,3H)；LC-MS278.0[M+H]⁺.

Step 3

6- ((1R,2S) -2-aminocyclohexylamino) -4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide

6-chloro-4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide (841mg, 3.03mmol) was dissolved in NMP (2mL) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (649mg, 3.03mmol) was added to the solution, and the reaction mixture was heated with stirring in an oil bath at 120 ℃ for 24 hours. A second equivalent of tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (649mg, 3.03mmol) was added and the reaction was continued for 72 hours. The mixture was cooled and then the NMP solvent was distilled off under high vacuum. The residue was dissolved in dichloromethane containing a few drops of methanol and passed through a pad of silica gel with 5% 9:1MeOH: NH₄OH in CH₂Cl₂The solution in (4) was eluted to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (5, 6-dimethylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate, which was mixed with 6-chloro-4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide. The mixture was suspended in CH₂Cl₂(3mL), then TFA (1.48g, 13.0mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and chromatographed (spherical silica gel, 20-45uM, 50g, VersaflashSupelco, 0-10% 9:1MeOH: NH)₄OH in CH₂Cl₂Solution of (1R,2S) -2-aminocyclohexylamino) -4- (5, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide was purified from the resulting residue in 20 min (550mg, 49% yield over two steps) as an off-white solid.¹H NMR(DMSO-d₆):11.48(s,1H),8.36(br.s.,1H),8.05(s,1H),7.60(br.s.,1H),7.47(d,J＝8.1Hz,1H),6.80(d,J＝8.1Hz,1H),6.73(d,J＝8.1Hz,1H),3.87(br.s.,1H),3.15(br.s.,1H),2.45(s,3H),2.20(s,3H),1.44-1.79(m,8H),1.32(br.s.,2H)；LC-MS356.1[M+H]⁺.

Example 16

6- ((1R,2S) -2-amino-cyclohexylamino) -4- (5-chloro-6-methyl-pyridin-2-ylamino) -pyridazine-3-carboxamide

Step 1

6-chloro-4- (5-chloro-6-methylpyridin-2-ylamino) pyridazine-3-carboxylic acid methyl ester

To the pressure tube were added methyl 4, 6-dichloropyridazine-3-carboxylate (2g, 9.66mmol) and 5-chloro-6-methylpyridin-2-amine (2.76g, 19.3 mmol). To the mixture was added acetonitrile (12mL) and the reaction mixture was heated with stirring at 130 ℃ for 1.5 days. After cooling to room temperature, the acetonitrile was removed in vacuo. The obtained residue was purified by chromatography (silica gel, 80g, 50 μm, from Analogix, 0% -5% acetone in dichloromethane, 20 min., maintenance 5% for 5 min, then gradient was increased from 5% to 10% over the next 20 min) to give methyl 6-chloro-4- (5-chloro-6-methylpyridin-2-ylamino) pyridazine-3-carboxylate (618mg, 20%) as an orange solid.¹H NMR (400MHz, chloroform-d) ppm10.70(br.s.,1H),9.18(s,1H),7.63(d, J ═ 8.34Hz,1H),6.78(d, J ═ 8.34Hz,1H),4.12(s,3H),2.66(s,3H),1.58(br.s., 1H); LC-MS313[ M + H [ ]]⁺.

Step 2

6-chloro-4- (5-chloro-6-methylpyridin-2-ylamino) pyridazine-3-carboxamide

To the pressure tube were added methyl 6-chloro-4- (5-chloro-6-methylpyridin-2-ylamino) pyridazine-3-carboxylate (600mg, 1.92mmol) and ammonia in methanolSolution (7M, 20mL, 140 mmol). The reaction mixture was heated to 50 ℃ and stirred for 18 hours. The mixture was cooled and concentrated in vacuo to give 6-chloro-4- (5-chloro-6-methylpyridin-2-ylamino) pyridazine-3-carboxamide (665mg crude, 116%%) as a yellow solid.¹H NMR (400MHz, chloroform-d) ppm11.69(br.s.,1H),9.18(s,1H),8.20(br.s.,1H),7.61(d, J ═ 8.59Hz,1H),6.77(d, J ═ 8.59Hz,1H),5.71(br.s.,1H),2.65(s,3H). LC-MS298[ M + H]⁺The material was used in the next step without further purification.

Step 3

6- ((1R,2S) -2-Aminocyclohexylamino) -4- (5-chloro-6-methylpyridin-2-ylamino) pyridazine-3-carboxylic acid Amines as pesticides

6-chloro-4- (5-chloro-6-methylpyridin-2-ylamino) pyridazine-3-carboxamide (600mg, 2.01mmol), (1S,2R) -2-aminocyclohexylcarbamic acid tert-butyl ester (863mg, 4.03mmol) and NMP (6mL) were added to a pressure tube to give a yellow suspension. The reaction mixture was stirred at 140 ℃ for 2.5 days. After cooling to room temperature, NMP was evaporated using Kugelrohr to give a brown viscous oil. The crude material was dissolved in dichloromethane and methanol and adsorbed onto silica gel. By chromatography (spherical silica gel, 20-45 μm,50g, Versaflash column, from Supelco, from 100% dichloromethane to 84:15.2:0.8 dichloromethane/methanol/NH)₄OH elution) to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (5-chloro-6-methylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (242.3mg) as a brown solid. The product was then dissolved in dichloromethane (3mL) and TFA (2.96g, 2mL, 26.0mmol) was added. The mixture was stirred at room temperature for 2 hours. Excess TFA and dichloromethane were removed in vacuo and purified by chromatography (spherical silica, 20-45 μm,50g, Versaflash, from Supelco, using a gradient of 0.05:0.95:99 NH)₄OH methanol dichloromethane-0.6: 11.4:88NH₄OH methanol dichloromethane elution over 40 min) purification of the residue obtained to give 6- ((1)R,2S) -2-aminocyclohexylamino) -4- (5-chloro-6-methylpyridin-2-ylamino) pyridazine-3-carboxamide (152mg, 4%) was a light brown solid.¹HNMR(400MHz,DMSO-d₆)ppm11.77(br.s.,1H),8.42(br.s.,1H),8.05(br.s.,1H),7.59-7.80(m,2H),6.78-6.99(m,2H),3.18(br.s.,1H),2.57(br.s.,4H),1.21-1.42(m,2H),1.20-1.81(m,8H).LC-MS376[M+H]⁺.

Example 17

Step 1

2-diazo-3-oxo-glutaric acid dimethyl ester

To a stirred solution of dimethyl 3-oxoglutarate (50.0g, 287.1mmol) and triethylamine (47.8mL, 344.5mmol) in acetonitrile (1.2L) was added 4-acetamidobenzenesulfonyl azide (69.0g, 287.1mmol) portionwise at 0 deg.C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour (silica gel TLC; ethyl acetate: hexane: 1:4, Rf: 0.3; KMnO was shown₄Activity). The reaction mixture was filtered and the filtrate was concentrated to give a viscous mass which was diluted with n-hexane (3L). The unwanted solid by-product was removed by filtration and the filtrate was concentrated under reduced pressure to give dimethyl 2-diazo-3-oxo-glutarate (50.0g, 87% crude yield) as a pale yellow liquid which was used in the next step without further purification.

Step 2

4, 6-dihydroxy-pyridazine-3-carboxylic acid methyl ester

A mixture of dimethyl 2-diazo-3-oxo-glutarate (50.0g, 249.8mmol) and triphenylphosphine (65.5g, 249.8mmol) in diethyl ether (500mL) was stirred at room temperature for 24 h. The organic solvent was removed under vacuum, then acetic acid (500mL) and water (50mL) were added to the residue, and the mixture was refluxed for 10 hours. The reaction mixture was concentrated under reduced pressure to give a viscous residue. Trituration with ethyl acetate yielded a yellow solid which was purified by chromatography (silica gel, 100-mesh 200 mesh, 1-5% methanol in dichloromethane) to give methyl 4, 6-dihydroxy-pyridazine-3-carboxylate (12.8g, 30%) as a yellow solid. LC-MS169.2[ M + H ]]⁺.

Step 3

4, 6-dichloro-pyridazine-3-carboxylic acid methyl ester

4, 6-dihydroxy-pyridazine-3-carboxylic acid methyl ester (10.5g, 61.7mmol) and POCl₃The mixture (70mL) was heated to 95 ℃ for 5 hours. Excess POCl was removed under reduced pressure₃The crude residue was then added to ice-water (250mL) and extracted with ethyl acetate (3 × 100 mL). The combined extracts were dried and then concentrated to give a crude residue which was purified by chromatography (silica gel, 100 mesh, 200 mesh, 30% ethyl acetate in hexane) to give methyl 4, 6-dichloro-pyridazine-3-carboxylate (9.2g, 72%) as an off-white solid. LC-MS 207.0[ M + H ]]⁺.

Step 4

6-chloro-4- (5, 6-dimethoxy-pyridin-2-ylamino) -pyridazine-3-carboxylic acid methyl ester

4, 6-dichloro-pyridazine-3-carboxylic acid methyl ester (1.0g, 4.83mmol) and 5, 6-dimethoxyA mixture of phenylpyridin-2-amines (968mg, 6.28mmol) was dissolved in acetonitrile (5mL) and heated at 70 ℃ for 16 h. The mixture was concentrated in vacuo and the crude material obtained was purified by chromatography (silica gel, 100 mesh, 10-70% ethyl acetate in hexane) to give methyl 6-chloro-4- (5, 6-dimethoxy-pyridin-2-ylamino) -pyridazine-3-carboxylate (830mg, 53%) as a yellow solid. LC-MS 325.2[ M + H ]]⁺.

Step 5

6-chloro-4- (5, 6-dimethoxy-pyridin-2-ylamino) -pyridazine-3-carboxamide

Methyl 6-chloro-4- (5, 6-dimethoxy-pyridin-2-ylamino) -pyridazine-3-carboxylate (1.7g, 5.2mmol) was suspended in a solution of ammonia in methanol (7N, 30.0mL, 210mmol) and the flask was sealed. After stirring at room temperature for 6 hours, the mixture was concentrated in vacuo to give 6-chloro-4- (5, 6-dimethoxy-pyridin-2-ylamino) -pyridazine-3-carboxamide (1.55g, 96%) as a yellow powder. LC-MS 310.4[ M + H ]]⁺.

Step 6

6- ((1R,2S) -2-Aminocyclohexylamino) -4- (5, 6-dimethoxypyridin-2-ylamino) pyridazine-3-carboxylic acid Amines as pesticides

Method A

To the pressure tube were added 6-chloro-4- (5, 6-dimethoxypyridin-2-ylamino) pyridazine-3-carboxamide (310mg, 1.00mmol), (1S,2R) -2-aminocyclohexylcarbamic acid tert-butyl ester (429mg, 2.00mmol) and NMP (4 mL). The reaction mixture was stirred at 140 ℃ for 18 hours, then NMP was distilled off at 120 ℃ under high vacuum using Kugelrohr to give a brown viscous oil. The crude oil was dissolved in dichloromethaneAnd methanol, then adsorbed onto silica gel and purified by chromatography (spherical silica gel, 20-45 μm, 11g, Versaflash, from Supelco, with 100% dichloromethane-88: 11.4:0.6 dichloromethane: methanol: NH)₄OH, 40 min) to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (5, 6-dimethoxypyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate as a brown viscous oil (291.3 mg). This was dissolved in dichloromethane (2mL) and TFA (740mg, 500. mu.L, 6.49mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. TFA and dichloromethane were removed in vacuo and chromatographed (spherical silica, 20-45 μm,50g, Versaflash from Supelco, 0.1:1.9:98 NH)₄OH methanol dichloromethane-0.6: 11.4:88NH₄Methanol dichloromethane elution, 40 min) the obtained residue was purified to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (5, 6-dimethoxypyridin-2-ylamino) pyridazine-3-carboxamide (81mg, 21%) as a light brown solid.¹H NMR(400MHz,DMSO-d₆)ppm11.33(br.s.,1H),8.34(br.s.,1H),7.59(br.s.,1H),7.46(s,1H),7.35(d,J＝8.08Hz,1H),6.70(d,J＝7.83Hz,1H),6.57(d,J＝8.34Hz,1H),3.95(s,3H),3.76(s,3H),3.10(br.s.,1H),2.03(br.s.,2H),1.18-1.78(m,8H),0.98-1.12(m,1H)；LC-MS388[M+H]⁺.

Method B

To 6-chloro-4- (5, 6-dimethoxypyridin-2-ylamino) pyridazine-3-carboxamide (500mg, 1.6mmol) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (692mg, 3.2mmol) in NMP (1.5mL) was added methoxytrimethylsilane (0.5mL, 3.6mmol), and the mixture was heated to 150 ℃ for 65 hours. The mixture was concentrated under high vacuum to give a viscous crude material which was purified by chromatography (silica gel, 100 mesh, 200 mesh, 1-10% methanol in dichloromethane) to give 6- ((1R,2S) -2-amino-cyclohexylamino) -4- (5, 6-dimethoxy-pyridin-2-ylamino) -pyridazine-3-carboxamide (220mg 35%) as a yellow solid. LC-MS388[ M + H ]]⁺.

Example 18

6- ((1R,2S) -2-aminocyclohexylamino) -4- (4, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

6-chloro-4- (4, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

To a mixture of ethyl 4, 6-dichloropyridazine-3-carboxylate (790mg, 3.57mmol) in acetonitrile (11.9mL) was added 4, 6-dimethylpyridin-2-amine (873mg, 7.15mmol) and heated in a sealed bottle at 140 ℃ for 20 h. The mixture was concentrated in vacuo and then purified by chromatography (silica gel, 0-8% acetone in dichloromethane) to give ethyl 6-chloro-4- (4, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxylate (165mg, 538 μmol, 15%) as an off-white solid.¹H NMR (400MHz, chloroform-d) ppm10.60(s,1H),9.24(s,1H),8.75(s,1H),8.59(s,1H),4.58(q, J ═ 7.1Hz,2H),2.53(s,3H),2.33(s,3H),1.52(t, J ═ 7.1Hz, 3H); MS (EI/CI) M/z 306.1[ M + H ]].

Step 2

6-chloro-4- (4, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide

To a solution of ethyl 6-chloro-4- (4, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxylate (165mg, 538. mu. mol) in methanol (1mL) was added a methanol solution of ammonia (4.72g, 6mL, 42.0mmol), and the mixture was stirred at 50 ℃ for 16 hours. The mixture was concentrated in vacuo to give 6-chloro-4- (4, 6-bis)

Methylpyridin-2-ylamino) pyridazine-3-carboxamide (140mg, 504. mu. mol, 94%) was a white solid.¹H NMR(400MHz,DMSO-d)ppm11.92(s,1H),9.13(s,1H),8.86(s,1H),8.21(s,1H),6.84(s,1H),6.76(s,1H),2.45(s,3H),2.29(s,3H)；MS(EI/CI)m/z:277.9[M+H].

Step 3

(1S,2R) -2- (6-carbamoyl-5- (4, 6-dimethylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexyl Carbamic acid tert-butyl ester

To a solution of 6-chloro-4- (4, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide (140mg, 504. mu. mol) in NMP (2.52mL) was added tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (216mg, 1.01mmol), and the mixture was heated at 130 ℃ for 72 hours. The reaction mixture was cooled and diluted with ethyl acetate and brine. The organic phase was washed with brine (2x) and water (1x), then concentrated in vacuo and purified by chromatography (silica gel, 40-100% ethyl acetate in hexanes) to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (4, 6-dimethylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (75mg, 98.8 μmol, 20%) as an orange solid. MS (EI/CI) M/z 456.2[ M + H ].

Step 4

6- ((1R,2S) -2-aminocyclohexylamino) -4- (4, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide 2,2, 2-Trifluoroacetate salt

To a solution of tert-butyl (1S,2R) -2- (6-carbamoyl-5- (4, 6-dimethylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (75mg, 165. mu. mol) in dichloromethane (5mL) was added trifluoroacetic acid (1.88g, 1.27mL, 16.5mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated, then the residue was diluted with dichloromethane and NH₄OH is neutralized. By chromatography (silica gel, 0-100% 10:0.5:89.5 formazan)Alcohol NH₄Dichloromethane solution of dichloromethane) and then further purified by HPLC (C-18, acetonitrile gradient of 10-100% water) to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (4, 6-dimethylpyridin-2-ylamino) pyridazine-3-carboxamide 2,2, 2-trifluoroacetate (33mg, 70.3 μmol, 43%) as a fluffy off-white solid.¹H NMR(400MHz,DMSO-d₆)ppm11.66(s,1H),8.38(s,1H),8.25(s,1H),7.86(br.s,1H),7.40(br.s,2H),6.76(s,1H),6.65(s,1H),4.40(s.,1H),3.63(s,1H),2.48(s,3H),1.58-1.86(m,8H),1.46(m,2H)；MS(EI/CI)m/z:356.1[M+H].

Example 19

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-tert-butylpyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

4- (6-tert-Butylpyridin-2-ylamino) -6-chloropyridazine-3-carboxylic acid methyl ester

A mixture of methyl 4, 6-dichloropyridazine-3-carboxylate (0.69g, 3.33mmol) and 6-tert-butylpyridin-2-amine (1.00g, 6.67mmol) was dissolved in acetonitrile (3mL) and heated at 130 ℃ for 14 h. The dark brown mixture was cooled, concentrated onto silica gel and purified by chromatography (silica gel, 80g, 0-20% acetone in dichloromethane, 40 min) to give methyl 4- (6-tert-butylpyridin-2-ylamino) -6-chloropyridazine-3-carboxylate (372mg, 1.16mmol, 35%) as a yellow solid. MS (EI/CI) M/z 321.0[ M + H ].

Step 2

4- (6-tert-butylpyridin-2-ylamino) -6-chloropyridazine-3-carboxamide

Methyl 4- (6-tert-butylpyridin-2-ylamino) -6-chloropyridazine-3-carboxylate (360mg, 1.12mmol) was suspended in a 7N solution of ammonia in methanol (12mL, 84.0mmol) and stirred at room temperature for 16 h. The mixture was concentrated in vacuo to give 4- (6-tert-butylpyridin-2-ylamino) -6-chloropyridazine-3-carboxamide (317mg, 1.03mmol, 92%) as a yellow powder. MS (EI/CI) M/z 306.0[ M + H ]. this material was used in the next step without further purification.

Step 3

(1S,2R) -2- (5- (6-tert-butylpyridin-2-ylamino) -6-carbamoylpyridazin-3-ylamino) cyclohexyl Carbamic acid tert-butyl ester

A stirred solution of 4- (6-tert-butylpyridin-2-ylamino) -6-chloropyridazine-3-carboxamide (317mg, 1.04mmol) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (444mg, 2.07mmol) in NMP (4mL) was heated at 140 ℃ in a sealed tube for 24 h. The mixture was concentrated in vacuo (kuglenohr, high vacuum) to afford a brown solid. Purification by chromatography (silica gel, 40g, 0-10% 9:1MeOH in dichloromethane, 30 min) followed by chromatography (silica gel, 24g, 10% acetone in dichloromethane, 10min, then 9:1:90MeOH: NH)₄OH: DCM, 10 min.) to give tert-butyl (1S,2R) -2- (5- (6-tert-butylpyridin-2-ylamino) -6-carbamoylpyridazin-3-ylamino) cyclohexylcarbamate (197mg, 407. mu. mol, 39%) as a brown viscous gum. MS (EI/CI) M/z 484.2[ M + H [ ]]The material contained a small amount of residual NMP and was used in the next step without further purification.

Step 4

To a solution of tert-butyl (1S,2R) -2- (5- (6-tert-butylpyridin-2-ylamino) -6-carbamoylpyridazin-3-ylamino) cyclohexylcarbamate (192mg, 397. mu. mol) in dichloromethane (2mL) was added TFA (747mg, 505. mu.L, 6.55 mmol). After 14 h, the mixture was concentrated in vacuo and then chromatographed (spherical silica, 50g, 0-20% 9:1MeOH: NH)₄OH in dichloromethane, 30 min) to give a light brown gum. It was triturated with ethanol and concentrated to give a yellow solid. Trituration was again with hot ethanol then the supernatant decanted to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-tert-butylpyridin-2-ylamino) pyridazine-3-carboxamide (57mg, 149 μmol, 37%) as a cream powder after drying under high vacuum.¹H NMR(DMSO-d₆):11.80(s,1H),8.39(d,J＝2.0Hz,1H),7.98(s,1H),7.55-7.76(m,2H),6.96-7.09(m,1H),6.77(dd,J＝8.1,0.5Hz,1H),6.70(d,J＝8.1Hz,1H),3.67(br.s.,1H),3.03-3.12(m,1H),1.45-1.72(m,8H),1.22-1.41(m,11H)；MS(EI/CI)m/z:384.2[M+H].

Example 20

6- (cyclohexylamino) -4- (6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide

A suspension of 6-chloro-4- (6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide (100mg, 345. mu. mol, prepared as described in example 12) and cyclohexylamine (342mg, 395. mu.L, 3.45mmol) in N-methyl-2-pyrrolidone (0.5mL) was heated at 130 ℃ for 14 h. The mixture was cooled and concentrated at 120 ℃ under high vacuum to remove all residual solvent and amine starting material. The brown solid obtained is purified by chromatography (silica gel, 11g spheres, 0-20% acetone in dichloromethane, 20 min) to give 6- (cyclohexylamino) -4- (6-ring)Propylpyridin-2-ylamino) pyridazine-3-carboxamide (81mg, 230. mu. mol, 67% yield) was a white solid.¹H NMR(DMSO-d₆):11.72(br.s.,1H),8.37(br.s.,1H),7.83(s,1H),7.62(br.s.,1H),7.56(t,J＝7.7Hz,1H),7.10(d,J＝7.8Hz,1H),6.88(d,J＝7.3Hz,1H),6.66(d,J＝8.1Hz,1H),3.52-3.69(m,1H),2.04-2.18(m,1H),1.90-2.00(m,2H),1.72-1.82(m,2H),1.63(d,J＝12.6Hz,1H),1.24-1.45(m,4H),1.09-1.23(m,1H),0.95-1.03(m,4H)；MS(EI/CI)m/z:353.1[M+H].

Example 21

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-cyclobutylpyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

6-chloro-4- (6-cyclobutylpyridin-2-ylamino) pyridazine-3-carboxylic acid methyl ester

To a thick-walled resealable tube was added methyl 4, 6-dichloropyridazine-3-carboxylate (1.3g, 6.28mmol) and 6-cyclobutylpyridin-2-amine (931mg, 6.28mmol) in acetonitrile (6.00 mL). The tube was heated with stirring in an oil bath at 80 ℃ for 48 hours. The solvent was evaporated in vacuo and the residue was dissolved in dichloromethane and purified by flash chromatography (spherical silica gel, 20-45 μ M,50g, Versaflash Supelco) eluting with 0-10% dichloromethane/acetone over 20 min to give methyl 6-chloro-4- (6-cyclobutylpyridin-2-ylamino) pyridazine-3-carboxylate (350mg, 17.5% yield) as a pale yellow solid.¹H NMR (chloroform-d) 10.62(s,1H),9.49(s,1H),7.59(t, J ═ 7.9Hz,1H),6.85(d, J ═ 7.6Hz,1H),6.73(d, J ═ 8.3Hz,1H),4.10(s,3H),3.67(quin, J ═ 8.6Hz,1H),2.24-2.58(m,4H),1.85-2.22(m, 2H); LC-MS319.0[ M + H [ ]]⁺.

Step 2

6-chloro-4- (6-cyclobutylpyridin-2-ylamino) pyridazinOxazine-3-carboxamides

In a 100mL round-bottom flask, methyl 6-chloro-4- (6-cyclobutylpyridin-2-ylamino) pyridazine-3-carboxylate (350mg, 1.1mmol) was suspended in a 7M solution of ammonia in methanol (7.87g, 10.0mL, 70.0 mmol). The flask was sealed and stirred at room temperature for 18 hours. The solid formed was isolated by filtration and dried in vacuo to give 6-chloro-4- (6-cyclobutylpyridin-2-ylamino) pyridazine-3-carboxamide (281mg, 84.3% yield) as a white solid.¹H NMR(DMSO-d₆):11.95(s,1H),9.34(s,1H),8.85(s,1H),8.20(s,1H),7.69(t,J＝7.7Hz,1H),6.91(dd,J＝7.7,3.6Hz,2H),3.66(quin,J＝8.6Hz,1H),2.19-2.40(m,4H),1.78-2.15(m,2H)；LC-MS304.1[M+H]⁺.

Step 3

(1S,2R) -2- (6-carbamoyl-5- (6-cyclobutylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylamino Benzoic acid tert-butyl ester

In a 25mL round bottom flask, a solution of 6-chloro-4- (6-cyclobutylpyridin-2-ylamino) pyridazine-3-carboxamide (281mg, 925 μmol) in N-methyl-2-pyrrolidone (3.5mL) was treated with tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (397mg, 1.85mmol) and the mixture was heated to 120 ℃ for 72 hours. After cooling to room temperature, the solvent is evaporated under high vacuum and the residue is purified by flash column (spherical silica gel, 20-45. mu.M, 80g, Versaflash Supelco) using 0-5% (containing 10% NH)₄MeOH/CH of OH₂Cl₂Elution was carried out for 20 minutes to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (6-cyclobutylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (112mg, 25.1% yield) as a light brown foam.¹H NMR (chloroform-d) 11.49(br.s.,1H),8.38(s,1H),8.12(d, J ═ 3.0Hz,1H),7.42(t, J ═ 7.9Hz,1H),7.23(s,1H),6.67(d, J ═ 7.2Hz,1H),6.59(d, J ═ 7.9Hz,1H),5.89-6.22(m,2H),3.72-4.08(m,2H),3.55(quin, J ═ 8.6Hz,1H),1.76-2.11(m,4H),1.19-1.74(m, 19H); LC-MS482.1[ M + H ]]⁺.

Step 4

In a 25mL round-bottom flask, (1S,2R) -tert-butyl 2- (6-carbamoyl-5- (6-cyclobutylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (112mg, 233. mu. mol) was added to CH₂Cl₂(5.0mL) was treated with TFA (2.22g, 1.5mL, 19.5mmol) and the mixture was stirred to room temperature for 18 h. The solvent was evaporated and the residue was purified by flash chromatography (spherical silica gel 20-45. mu.M, 80g, Versaflash Supelco) using 0-10% (containing 10% NH)₄MeOH/CH of OH₂Cl₂Elution was carried out for 30 min to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-cyclobutylpyridin-2-ylamino) pyridazine-3-carboxamide (48mg, 126. mu. mol, 54.1% yield) as an off-white solid.¹H NMR (chloroform-d) 11.43(br.s.,1H),8.45(s,1H),8.03(br.s.,1H),7.51(t, J ═ 7.7Hz,1H),6.75(d, J ═ 7.2Hz,1H),6.68(d, J ═ 7.9Hz,1H),5.62(d, J ═ 8.3Hz,1H),5.37(br.s.,1H),3.88(br.s.,1H),3.65(quin, J ═ 8.5Hz,1H),3.22(d, J ═ 4.9Hz,1H),2.27-2.51(m,4H),1.99-2.22(m,1H),1.94(dd, J ═ 11.s., 1,5, 1H), 1.84 (1.07H); LC-MS382.0[ M + H [ ]]⁺.

Example 22

6- ((1R,2S) -2-aminocyclohexylamino) -4- (1-methyl-1H-benzo [ d ] imidazol-4-ylamino) pyridazine-3-carboxamide

Step 1

6-chloro-4- (1-methyl-1H-benzo [ d)]Imidazol-4-ylamino) pyridazine-3-carboxylic acid ethyl ester

To a thick-walled resealable tube was added ethyl 4, 6-dichloropyridazine-3-carboxylate (500mg, 2.26mmol) and 1-methyl-1H-benzo [ d ] in acetonitrile (3.5mL) with stirring]Imidazol-4-amine dihydrochloride (498mg, 2.26 mmol). DIPEA (877mg, 1.19mL, 6.79mmol) was added and the tube was heated with stirring in an oil bath at 80 ℃ for 24 hours. Evaporation of the solvent and purification of the crude material by flash chromatography (silica gel 20-45. mu.M, 80g, Thomson, 0-20% acetone in dichloromethane, 20 min.) gives 6-chloro-4- (1-methyl-1H-benzo [ d [) 2]Imidazol-4-ylamino) pyridazine-3-carboxylic acid ethyl ester (461mg, 1.39mmol, 61%) as a pale yellow solid.¹H NMR (chloroform-d) 10.42(s,1H),7.92(s,1H),7.30-7.45(m,2H),7.23-7.28(m,1H),7.20(s,1H),4.59(q, J ═ 7.1Hz,2H),3.91(s,3H),1.51(t, J ═ 7.2Hz, 3H); LC-MS332.0[ M + H ]]⁺.

Step 2

6-chloro-4- (1-methyl-1H-benzo [ d)]Imidazol-4-ylamino) pyridazine-3-carboxamides

Reacting 6-chloro-4- (1-methyl-1H-benzo [ d ]]Imidazol-4-ylamino) pyridazine-3-carboxylic acid ethyl ester (285mg, 859. mu. mol) was suspended in ammonia (7M in methanol, 7.87g, 10.0mL, 70.0 mmol). The flask was sealed and stirred at room temperature for 18 hours. The solvent is evaporated and the residue is dried under high vacuum to give 6-chloro-4- (1-methyl-1H-benzo [ d ]]Imidazol-4-ylamino) pyridazine-3-carboxamide (260mg, 100%) as an off-white solid.¹H NMR(DMSO-d₆):11.36(s,1H),8.74(s,1H),8.22(s,1H),8.09(s,1H),7.41-7.52(m,1H),7.28-7.35(m,2H),7.23(s,1H),3.86(s,3H)；LC-MS303.0[M+H]⁺.

Step 3

Reacting 6-chloro-4- (1-methyl-1H-benzo [ d ]]A solution of imidazol-4-ylamino) pyridazine-3-carboxamide (260mg, 859. mu. mol) in N-methyl-2-pyrrolidone (3.0mL) was treated with tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (368mg, 1.72mmol) and the mixture was heated to 120 ℃ for 72 hours. The solvent was evaporated under high vacuum and chromatographed (spherical silica gel 20-45. mu.M, 80g, VersaflashSupelco, 0-5% 9:1MeOH: NH)₄CH of OH₂Cl₂Solution, 20 min) to give (1S,2R) -2- (6-carbamoyl-5- (1-methyl-1H-benzo [ d)]Imidazol-4-ylamino) pyridazin-3-ylamino) cyclohexylcarbamic acid tert-butyl ester (132mg, 32%) as a light brown foam.¹H NMR (chloroform-d) 11.05(s,1H),7.89(d, J ═ 2.6Hz,1H),7.77(s,1H),7.39(br.s.,1H),6.96-7.30(m,3H),6.40(br.s.,1H),6.10-6.33(m,2H),3.78(br.s.,4H),3.52(br.s.,1H),0.95-1.70(m, 17H); LC-MS481.0[ M + H [ ]]⁺.

Step 4

6- ((1R,2S) -2-aminocyclohexylamino) -4- (1-methyl-1H-benzo [ d)]Imidazol-4-ylamino) pyridazine- 3-carboxamides

Reacting (1S,2R) -2- (6-carbamoyl-5- (1-methyl-1H-benzo [ d ]]Imidazol-4-ylamino) pyridazin-3-ylamino) cyclohexylcarbamic acid tert-butyl ester (132mg, 275. mu. mol) in CH₂Cl₂(5mL) solution in TFA (4.0)8g, 2.76mL, 35.8mmol) and the reaction mixture was stirred to room temperature for 18 hours. The solvent was evaporated and chromatographed (spherical silica gel 20-45. mu.M, 80g, Versaflash Supelco, 0-10% 9:1MeOH: NH)₄CH of OH₂Cl₂Solution, 30 min) purification of the residue to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (1-methyl-1H-benzo [ d)]Imidazol-4-ylamino) pyridazine-3-carboxamide (70mg, 67%) as an off-white solid.¹H NMR(DMSO-d₆):11.06(s,1H),8.23(br.s.,1H),8.16(s,1H),7.50(br.s.,1H),7.15-7.37(m,3H),6.75(s,1H),6.70(d,J＝7.6Hz,1H),4.09(br.s.,1H),3.84(s,3H),3.08(br.s.,1H),1.54(br.s.,6H),1.26(d,J＝17.0Hz,2H)；LC-MS381.1[M+H]⁺.

Example 23

4- (6- (2H-1,2, 3-triazol-2-yl) pyridin-2-ylamino) -6- ((1R,2S) -2-aminocyclohexylamino) pyridazine-3-carboxamide

Step 1

4- (6- (2H-1,2, 3-triazol-2-yl) pyridin-2-ylamino) -6-chloropyridazin-3-carboxylic acid ethyl ester

To a solution of 4, 6-dichloropyridazin-3-carboxylic acid ethyl ester (154mg, 695. mu. mol) in acetonitrile was added 6- (2H-1,2, 3-triazol-2-yl) pyridin-2-amine (112mg, 695. mu. mol) and heated to 140 ℃ for 72 hours. The mixture was cooled and precipitated by adding acetone. The mixture was filtered and the collected solid was washed with methanol and ether then dried to give ethyl 4- (6- (2H-1,2, 3-triazol-2-yl) pyridin-2-ylamino) -6-chloropyridazine-3-carboxylate (85mg, 246 μmol, 35%) as an off-white solid.¹H NMR(400MHz,DMSO-d)ppm10.60(s,1H),9.50(s,1H),8.26(s,2H),8.08(t,J＝8.2Hz,1H),7.74(d,J＝7.8Hz,1H),7.35(d,J＝8.2Hz,1H),4.48(q,J＝7.3Hz,2H),1.40(t,J＝7.3Hz,3H)；MS(EI/CI)m/z:346.0[M+H].

Step 2

4- (6- (2H-1,2, 3-triazol-2-yl) pyridin-2-ylamino) -6-chloropyridazine-3-carboxamide

A methanol solution of ammonia (3.94g, 5mL, 35.0mmol) was added to ethyl 4- (6- (2H-1,2, 3-triazol-2-yl) pyridin-2-ylamino) -6-chloropyridazine-3-carboxylate (100mg, 289. mu. mol) and stirred at 35 ℃ for 16H. The mixture was concentrated in vacuo to give 4- (6- (2H-1,2, 3-triazol-2-yl) pyridin-2-ylamino) -6-chloropyridazin-3-carboxamide (90mg, 284 μmol, 98%) as an off-white solid.¹H NMR(400MHz,DMSO-d)ppm12.30(s,1H),9.13(s,1H),9.54(s,1H),8.94(s,1H),8.29(s,1H),8.27(s,2H),8.05(t,J＝8.1Hz,1H),7.72(d,J＝7.9Hz,1H),7.23(d,J＝8.1Hz,1H)；MS(EI/CI)m/z:316.9[M+H].

Step 3

(1S,2R) -2- (5- (6- (2H-1,2, 3-triazol-2-yl) pyridin-2-ylamino) -6-carbamoylpyridazine- 3-ylamino) cyclohexyl carbamic acid tert-butyl ester

To a solution of 4- (6- (2H-1,2, 3-triazol-2-yl) pyridin-2-ylamino) -6-chloropyridazine-3-carboxamide (90mg, 284. mu. mol) in NMP (947. mu.L) was added tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (122mg, 568. mu. mol) and the mixture was heated to 140 ℃ for 16 hours. Additional tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (61mg, 284. mu. mol) was added and the mixture was heated for a further 16 hours. The reaction mixture was cooled, diluted with ethyl acetate and brine, then the layers were separated and the organic phase was collected and washed with brine (2 ×). The organic layer was concentrated in vacuo and then purified by chromatography (silica gel, 2-5% methanol in dichloromethane) to give a residue which was triturated with ethyl acetate, filtered and washed with ether to give tert-butyl (1S,2R) -2- (5- (6- (2H-1,2, 3-triazol-2-yl) pyridin-2-ylamino) -6-carbamoylpyridazin-3-ylamino) cyclohexylcarbamate (79mg, 160 μmol, 56%) as a brown solid. MS (EI/CI) M/z 495.1[ M + H ].

Step 4

4- (6- (2H-1,2, 3-triazol-2-yl) pyridin-2-ylamino) -6- ((1R,2S) -2-aminocyclohexylamino) Pyridazine-3-carboxamides

To a solution of tert-butyl (1S,2R) -2- (5- (6- (2H-1,2, 3-triazol-2-yl) pyridin-2-ylamino) -6-carbamoylpyridazin-3-ylamino) cyclohexylcarbamate (79mg, 160. mu. mol) in dichloromethane (2.5mL) was added trifluoroacetic acid (364mg, 246. mu.L, 3.19mmol) and the mixture was stirred at room temperature for 16H. The mixture was diluted with dichloromethane and 1N NaOH (2mL) and then NaHCO₃And a brine wash. The organic layer was MgSO₄Dried, then filtered and concentrated in vacuo. The mixture was dissolved in ethanol and concentrated (3 ×). The obtained residue was triturated with ether and finally filtered to give 4- (6- (2H-1,2, 3-triazol-2-yl) pyridin-2-ylamino) -6- ((1R,2S) -2-aminocyclohexylamino) pyridazine-3-carboxamide (5mg, 10.8 μmol, 7%) as a light brown solid.¹H NMR(400MHz,DMSO-d₆)ppm12.12(s,1H),8.46(s,1H),8.38(s,2H),7.99(t,J＝8.1Hz,1H),7.80(s,1H),7.62(d,J＝8.1Hz,1H),7.11(d,J＝8.2Hz,1H),6.94(s.,1H),1.35-1.85(m,8H),1.46(m,2H)；MS(EI/CI)m/z:395.1[M+H].

Example 24

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6, 7-dihydro-5H-cyclopenta [ b ] pyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

6-chloro-4- (6, 7-dihydro-5H-cyclopenta [ b)]Pyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

Adding 4, 6-dichloropyridazine-3-carboxylic acid ethyl ester (1.5g, 6.79mmol) and 6, 7-dihydro-5H-cyclopenta [ b ] into a thick-wall resealable tube]Pyridin-2-amine (1.09g, 8.14mmol), acetonitrile (10mL), and quinine (Hunig's base) (877mg, 1.19mL, 6.79 mmol). The mixture was heated with stirring at 80 ℃ for 3 days, cooled to room temperature, the solvent was evaporated off and the crude residue obtained was purified by chromatography (80g column, 50. mu.M in 0-10% acetone in dichloromethane, 20 min, from Thomson) to give 6-chloro-4- (6, 7-dihydro-5H-cyclopenta [ b ]]Pyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester (554mg, 26%) was a light brown solid.¹H NMR (chloroform-d) 10.51(s,1H),8.94(s,1H),7.41(d, J ═ 8.3Hz,1H),6.60(d, J ═ 8.3Hz,1H),4.46(q, J ═ 7.2Hz,2H),2.92(t, J ═ 7.7Hz,2H),2.83(t, J ═ 7.4Hz,2H),1.87-2.24(m,2H),1.42(t, J ═ 7.2Hz, 3H); LC-MS319.0[ M + H [ ]]⁺.

Step 2

6-chloro-4- (6, 7-dihydro-5H-cyclopenta [ b)]Pyridin-2-ylamino) pyridazine-3-carboxamides

Reacting 6-chloro-4- (6, 7-dihydro-5H-cyclopenta [ b ]]Pyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester (554mg, 1.74mmol) was suspended in 7M ammonia in methanol (11.8g, 15.0mL, 105 mmol). The flask containing the mixture was sealed and stirred at room temperature for 18 hours. The precipitated off-white solid was isolated by filtration and dried under high vacuum to give 6-chloro-4- (6, 7-dihydro-5H-cyclopenta [ b ]]Pyridin-2-ylamino) pyridazine-3-carboxamide (375mg, 75%) as an off-white solid.¹H NMR(DMSO-d₆):11.92(s,1H),8.95(s,1H),8.83(s,1H),8.18(s,1H),7.63(d,J＝7.9Hz,1H),6.84(d,J＝7.9Hz,1H),2.78-3.00(m,4H),2.07(quin,J＝7.6Hz,2H)；LC-MS290.0[M+H]⁺.

Step 3

(1S,2R) -2- (6-carbamoyl-5- (6, 7-dihydro-5H-cyclopenta [ b)]Pyridin-2-ylamino) pyridazine- 3-ylamino) cyclohexyl carbamic acid tert-butyl ester

Reacting 6-chloro-4- (6, 7-dihydro-5H-cyclopenta [ b ]]A solution of pyridin-2-ylamino) pyridazine-3-carboxamide (375mg, 1.29mmol) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (555mg, 2.59mmol) in N-methyl-2-pyrrolidone (3mL) was treated with tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (555mg, 2.59 mmol). The reaction mixture was heated at 120 ℃ for 72 hours, then cooled to room temperature, concentrated under high vacuum, and the residue obtained was purified by chromatography (spherical silica gel 20-45. mu.M, 80g, Versaflash Supelco, 0-5% 9:1MeOH: NH)₄CH of OH₂Cl₂Solution, 20 minutes) to give (1S,2R) -2- (6-carbamoyl-5- (6, 7-dihydro-5H-cyclopenta [ b)]Pyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamic acid tert-butyl ester (444mg, 73%) as a light brown foam.¹H NMR (chloroform-d) 11.30(s,1H),8.19(s,1H),8.06(d, J ═ 3.4Hz,1H),7.40(d, J ═ 8.3Hz,1H),6.75-7.10(m,1H),6.61(d, J ═ 8.3Hz,1H),5.77-6.14(m,2H),3.99(m,1H),3.55-3.74(m,1H),2.67-3.05(m,4H),2.11(quin, J ═ 7.5Hz,2H),1.18-2.01(m, 17H); LC-MS468.2[ M + H [ ]]⁺.

Step 4

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6, 7-dihydro-5H-cyclopenta [ b)]Pyridin-2-ylamino Yl) pyridazine-3-carboxamides

Mixing (1S,2R) -2- (6-carbamoyl-5- (6, 7-dihydro-5H-cyclopenta [ b ]]Pyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamic acid tert-butyl ester (444mg, 950. mu. mol) in CH₂Cl₂A solution in (5mL) was treated with TFA (4.08g, 2.76mL, 35.8mmol) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue was purified by flash chromatography (spherical silica gel 20-45. mu.M, 80g, Versaflash Supelco) with 0-5% 9:1MeOH: NH₄CH of OH₂Cl₂Solution elution, 15 min) gave 6- ((1R,2S) -2-aminocyclohexylamino) -4- (6, 7-dihydro-5H-cyclopenta [ b)]Pyridin-2-ylamino) pyridazine-3-carboxamide (80mg, 23%) as an off-white solid.¹H NMR(DMSO-d₆):11.54(br.s.,1H),8.35(br.s.,1H),7.95(br.s.,1H),7.46-7.69(m,2H),6.80(d,J＝7.2Hz,1H),6.69(d,J＝7.6Hz,1H),3.89(br.s.,1H),3.12(br.s.,1H),2.75-2.98(m,4H),1.96-2.17(m,2H),1.61(d,J＝11.7Hz,8H),1.31(br.s.,2H)；LC-MS368.3[M+H]⁺.

Example 25

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

6-chloro-4- (6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

To a thick-walled sealable tube was added ethyl 4, 6-dichloropyridazine-3-carboxylate (0.985g, 4.46mmol) and 6-isopropyl-5-methylpyridin-2-amine (1.005g, 6.69 mmol). Acetonitrile (5mL) was added to the mixture and the yellow solution was heated with stirring (oil bath/hot plate) at 130 ℃ for 20 hours to give a brown solution. Cooling to room temperatureAfter that, acetonitrile was removed in vacuo to obtain a dark brown solid. The residue was dissolved in dichloromethane, adsorbed onto silica gel and purified by flash column (spherical silica gel 20-45 μm,50g, Versaflash, ex Supelco, eluting with 0% -5% acetone in dichloromethane, over 20 minutes, holding for 5 minutes; then 5% -20%, holding for 20, holding for 5 minutes) to give ethyl 6-chloro-4- (6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxylate as yellow crystals (848mg, 57%).¹H NMR (400MHz, chloroform-d) ppm10.60(br.s.,1H),9.36(s,1H),7.44(d, J ═ 8.08Hz,1H),6.70(d, J ═ 8.08Hz,1H),4.58(q, J ═ 7.07Hz,2H),3.30(spt, J ═ 6.70Hz,1H),2.34(s,3H),1.52(t, J ═ 7.20Hz,3H),1.33(d, J ═ 6.82Hz,6H), LC-MS335[ M + H [, ] M]⁺.

Step 2

6-chloro-4- (6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxamide

Ethyl 6-chloro-4- (6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxylate (850mg, 2.54mmol) and a solution of ammonia in methanol (7M, 20mL, 140mmol) were added to a pressure tube. The pale yellow suspension was stirred at 50 ℃ for 1.5 hours. After this time, the reaction mixture was concentrated in vacuo to give 6-chloro-4- (6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxamide (693mg, 89%) as an orange solid.¹H NMR (400MHz, chloroform-d) ppm11.48(br.s.,1H),9.39(s,1H),8.18(br.s.,1H),7.42(d, J ═ 8.08Hz,1H),6.71(d, J ═ 8.08Hz,1H),5.67(br.s.,1H),3.29(dt, J ═ 13.52,6.63Hz,1H),2.33(s,3H),2.26-2.26(M,1H),1.33(d, J ═ 6.82Hz,2H), LC-MS306[ M + H ], (M,1H) }]⁺.

Step 3

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-isopropyl-5-methylpyridin-2-ylamino) pyridazin-3- Carboxamides

6-chloro-4- (6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxamide (230mg, 752. mu. mol), (tert-butyl 1S,2R) -2-aminocyclohexylcarbamate (242mg, 1.13mmol) and NMP (4mL) were added to the pressure tube. The yellow solution was stirred at 130 ℃ for 2.5 days. NMP was then evaporated off under high vacuum using a Kugelrohr apparatus to give a light brown solid. The crude solid was dissolved in dichloromethane and MeOH and adsorbed on silica gel and then purified by flash column (spherical silica gel 20-45 μm, 11g, Versaflash, from Supelco, using 100% dichloromethane-88: 11.4:0.6 dichloromethane: methanol: NH)₄OH eluted over 40 minutes) to yield a light brown solid. The crude product was dissolved in dichloromethane (2mL) and TFA (740mg, 500. mu.L, 6.49mmol) was added. The mixture was stirred at room temperature for 4 hours. After that, TFA and dichloromethane were removed in vacuo, the brown solid obtained was dissolved in dichloromethane, adsorbed onto silica gel and then purified by flash column (spherical silica 20-45 μm, 11g, Versaflash, from Supelco, 100% dichloromethane-88: 11.4:0.6 dichloromethane: methanol: NH)₄OH eluted over 40 min) to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxamide (70mg, 24%) as a white solid.¹H NMR(400MHz,DMSO-d₆)ppm11.65(br.s.,1H),8.37(br.s.,1H),7.92(s,1H),7.61(br.s.,1H),7.48(d,J＝8.34Hz,1H),6.71(d,J＝8.08Hz,1H),6.66(d,J＝8.08Hz,1H),3.24(dt,J＝13.39,6.70Hz,1H),3.08(d,J＝2.53Hz,1H),2.26(s,3H),1.30-1.75(m,11H),1.26(dd,J＝6.70,1.39Hz,6H).LC-MS384[M+H]⁺.

Example 26

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-propylpyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

6-chloro-4- (6-propylpyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

A mixture of ethyl 4, 6-dichloropyridazine-3-carboxylate (0.80g, 3.62mmol) and 6-propylpyridin-2-amine (739mg, 5.43mmol) was dissolved in acetonitrile (4mL) and heated at 130 ℃. After 24 h, the reaction mixture was cooled and concentrated in vacuo, then purified by chromatography (silica gel, 80g, 0-3% acetone in dichloromethane over 15 min; then 3-10% acetone in dichloromethane over 15 min) to give ethyl 6-chloro-4- (6-propylpyridin-2-ylamino) pyridazine-3-carboxylate (335mg, 1.04mmol, 29%) as a pale yellow crystalline solid after drying at room temperature under high vacuum. LC-MS321.1[ M + H [ ]]⁺.

Step 2

6-chloro-4- (6-propylpyridin-2-ylamino) pyridazine-3-carboxamide

Ethyl 6-chloro-4- (6-propylpyridin-2-ylamino) pyridazine-3-carboxylate (340mg, 1.06mmol) was stirred with 7N methanolic ammonia (15.1mL, 106 mmol). A colorless precipitate formed within a few minutes. After 18 h, the mixture was concentrated in vacuo to give 6-chloro-4- (6-propylpyridin-2-ylamino) pyridazine-3-carboxamide (289mg, 991. mu. mol, 94%) as an off-white powder. LC-MS292.2[ M + H [ ]]⁺The material was used without purification.

Step 3

(1S,2R) -2- (6-carbamoyl-5- (6-propylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylamino (iv) Carboxylic acid tert-butyl ester

6-chloro-4- (6-propylpyridin-2-ylamino) pyridazine-3-carboxamide (289mg, 991. mu. mol) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (425mg, 1.98mmol) were dissolved in N-methyl-2-pyrrolidone (2mL) and heated at 130 ℃ for 24 hours. LCMS showed desired product quality and starting material. A third equivalent of tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (213mg, 0.991mmol) was added and heating continued. After 8 hours, a third portion of tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (0.310g) was added. After 24 hours, the mixture was cooled and concentrated in vacuo (high vacuum, 100 ℃) to a brown solid residue. Purification by chromatography (silica gel, 0-10% 9:1MeOH: NH)₄OH in dichloromethane for 20 min) to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (6-propylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (271mg, 577. mu. mol, 58%) as a light brown solid. LC-MS470.2[ M + H ]]⁺.

Step 4

Tert-butyl (1S,2R) -2- (6-carbamoyl-5- (6-propylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (260mg, 554. mu. mol) was dissolved in dichloromethane (4mL) and TFA (3.16g, 2.13mL, 27.7mmol) was added. The mixture was stirred at room temperature for 12 hours, then the mixture was concentrated in vacuo to a brown oil and purified by chromatography (silica gel, 40g, 0-20% 9:1MeOH: NH)₄OH in dichloromethane, 30 min) to give a pale yellow foam (140 mg). It was dissolved in ethanol and concentrated in vacuo (3 × 20mL) to give the desired product, H NMR and LCMS pure, except for traces of isopropanol. It was dissolved in anhydrous ethanol, concentrated in vacuo, then triturated twice with ethanol (2x0.5mL) and then dried to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-propan-ePyridylbidin-2-ylamino) pyridazine-3-carboxamide (110mg, 295. mu. mol, 53%) as a white powder.¹H NMR(DMSO-d₆):11.67(s,1H),8.39(br.s.,1H),8.08(br.s.,1H),7.63(t,J＝7.7Hz,2H),6.85(d,J＝7.6Hz,1H),6.72-6.82(m,2H),3.74(br.s.,1H),3.12(d,J＝3.0Hz,1H),2.65-2.76(m,2H),1.45-1.81(m,10H),1.21-1.39(m,2H),0.94(t,J＝7.3Hz,3H)；LC-MS370.2[M+H]⁺.

Example 27

6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxamide

6-chloro-4- (6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxamide (223mg, 729. mu. mol, prepared as described in example 25), (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamic acid tert-butyl ester (315mg, 1.46mmol) and NMP (4mL) were stirred at 140 ℃ for 18H. NMP was evaporated under high vacuum using a Kugelrohr apparatus to give a light brown solid. The crude material was dissolved in dichloromethane and MeOH and adsorbed on silica gel and then purified by chromatography (spherical silica gel 20-45 μm, 11g, Versaflash, from Supelco, using 100% dichloromethane-88: 11.4:0.6 dichloromethane: methanol: NH)₄OH elution over 40 min) gave 109mg of intermediate as a brown solid. This intermediate was dissolved in dichloromethane (2mL) and TFA (740mg, 500 μ L, 6.49mmol) was added. The mixture was stirred at room temperature for 16 hours. The TFA and dichloromethane were concentrated in vacuo and the resulting residue was purified by chromatography (spherical silica 20-45 μm, 11g, Versaflash, from Supelco, 100% dichloromethane-88: 11.4:0.6 dichloromethane: methanol: NH)₄OH eluted over 40 min) to yield a brown solid. The solid was suspended in 0.5mL heptane and 10 drops ethanol. The mixture was briefly sonicated, then heated, then cooled and the solvent decanted. Drying the solid residue under high vacuum overnight to obtainTo 6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxamide (22mg, 8%) as a brown solid.¹H NMR (400MHz, chloroform-d) ppm11.18-11.31(m,1H),8.26(s,1H),7.95(br.s.,1H),7.26(d, J ═ 8.34Hz,1H),6.55(d, J ═ 8.08Hz,1H),5.73(d, J ═ 7.33Hz,1H),5.29(br.s.,1H),3.99(br.s.,1H),3.90(d, J ═ 8.08Hz,1H),3.78(d, J ═ 11.37Hz,1H),3.66(q, J ═ 7.07Hz,1H),3.57(d, J ═ 11.37Hz,1H),3.44(t, J ═ 11.12, 1H),3.7 (J ═ 7.07Hz,1H),3.57(d, J ═ 11.37Hz,1H),3.44(t, J ═ 11.12, 1H), 3.dt ═ 7, 1H, 7.7, 1H),3.7, 1H, 7.7, 1H, 7, 7.7, 7H, 1H, 7H, 1H, 7H, 1H, 7H; LC-MS386[ M + H ]]⁺.

Example 28

6- ((1R,2S) -2-aminocyclohexylamino) -4- (3, 5-dimethylphenylamino) pyridazine-3-carboxamide

Step 1

6-chloro-4- (3, 5-dimethylphenylamino) pyridazine-3-carboxylic acid ethyl ester

To a solution of ethyl 4, 6-dichloropyridazine-3-carboxylate (700mg, 3.17mmol) in acetonitrile (10.6mL) was added ethyl 4, 6-dichloropyridazine-3-carboxylate (700mg, 3.17mmol), and the mixture was heated in a sealed bottle at 140 ℃ for 48 hours. The mixture was cooled and then concentrated in vacuo and purified by chromatography (silica gel, 0-30% acetone in dichloromethane) to give ethyl 6-chloro-4- (3, 5-dimethylphenylamino) pyridazine-3-carboxylate (104mg, 340. mu. mol, 11%) as a light brown solid.¹H NMR (400MHz, chloroform-d) ppm9.70(s,1H),7.03(s,1H),6.99(s,1H),6.88(s,2H),4.57(q, J ═ 7.6Hz,2H),2.38(s,6H),1.52(t, J ═ 7.6Hz, 3H); MS (EI/CI) M/z 305.9[ M + H ]].

Step 2

6-chloro-4- (3, 5-di)Methylphenylamino) pyridazine-3-carboxamides

To a solution of 6-chloro-4- (3, 5-dimethylphenylamino) pyridazine-3-carboxylic acid ethyl ester (104mg, 340. mu. mol) in methanol was added a methanol solution of ammonia (4.86mL, 34.0mmol), and the mixture was stirred at 50 ℃ for 16 hours. The mixture was concentrated to give 6-chloro-4- (3, 5-dimethylphenylamino) pyridazine-3-carboxamide (90mg, 325 μmol, 96%) as a brown solid, which was used without purification.¹H NMR(400MHz,DMSO-d)ppm10.84(s,1H),8.72(s,1H),8.08(s,1H),7.12(s,1H),6.98(s,2H),6.98(s,1H),6.93(s,1H),2.30(s,6H)；MS(EI/CI)m/z:276.9[M+H].

Step 3

(1S,2R) -2- (6-carbamoyl-5- (3, 5-dimethylphenylamino) pyridazin-3-ylamino) cyclohexylamino (iv) Carboxylic acid tert-butyl ester

To a solution of 6-chloro-4- (3, 5-dimethylphenylamino) pyridazine-3-carboxamide (44mg, 159. mu. mol) in NMP (530. mu.L) was added tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (68.2mg, 318. mu. mol), and the mixture was heated to 140 ℃ for 20 hours. Additional tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (68.2mg, 318. mu. mol) was then added and heating continued for an additional 7 hours. Finally, another portion of tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (34.1mg, 159. mu. mol) was added and the mixture was heated for 16 hours. The reaction mixture was cooled and then diluted with ethyl acetate. The layers were separated and the organic phase was washed with water and brine. The organic phases were collected, concentrated in vacuo, and the resulting residue was purified by chromatography (silica gel, 30-70% ethyl acetate in hexanes) to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (3, 5-dimethylphenylamino) pyridazin-3-ylamino) cyclohexylcarbamate (30mg, 66.0 μmol, 42%) as a brown oil. MS (EI/CI) M/z 455.2[ M + H ].

Step 4

To a solution of tert-butyl (1S,2R) -2- (6-carbamoyl-5- (3, 5-dimethylphenylamino) pyridazin-3-ylamino) cyclohexylcarbamate (30mg, 66.0. mu. mol) in dichloromethane (1mL) was added trifluoroacetic acid (151mg, 102. mu.L, 1.32mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, then diluted with dichloromethane and a few drops of 25% NH were added₄OH until pH was measured to 8. The weakly alkaline solution was washed with water, then the organic phase was concentrated in vacuo and purified by chromatography (silica gel, 30-100% 10:89.5:0.5MeOH: dichloromethane: NH)₄A solution of OH in dichloromethane) to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (3, 5-dimethylphenylamino) pyridazine-3-carboxamide (17mg, 48.0 μmol, 73%) as a light brown solid.¹H NMR (400MHz, methanol-d)₆)ppm6.90(s,2H),6.88(s,1H),6.50(s,1H),4.32(s,1H),1.63-1.84(m,6H),1.51(m,2H)；MS(EI/CI)m/z:355.1[M+H].

Example 29

6- ((3R,4R) -3-Aminotetrahydro-2H-pyran-4-ylamino) -4- (6-tert-butylpyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

4- (6-tert-Butylpyridin-2-ylamino) -6-chloropyridazine-3-carboxylic acid ethyl ester

4, 6-dichloropyridazine-3-carboxylic acid ethyl ester (0.73g, 3.3mmol) and 6-tert-butylpyridin-2-amine (992mg, 6.61mmol, available from J)&W PharmLab, LLC) was dissolved in acetonitrile (3.00mL) and heated at 130 ℃ for 20 hours. After cooling to room temperature, the mixture was concentrated and the residue was purified by flash chromatography (spherical silica gel 20-45 μ M,50g, VersaflashSupelco) eluting with 0-20% acetone in dichloromethane to give ethyl 4- (6-tert-butylpyridin-2-ylamino) -6-chloropyridazine-3-carboxylate (539mg, 48.7% yield) as a light brown residue over 20 minutes.¹H NMR (chloroform-d) 10.59(s,1H),9.32(s,1H),7.55(t, J ═ 7.9Hz,1H),6.98(d, J ═ 7.2Hz,1H),6.66(d, J ═ 7.9Hz,1H),4.48(q, J ═ 7.2Hz,2H),1.43(t, J ═ 7.2Hz,3H),1.28-1.35(m, 9H); LC-MS335.0,337.0[ M + H [ ]]⁺.

Step 2

4- (6-tert-butylpyridin-2-ylamino) -6-chloropyridazine-3-carboxamide

In a 100mL round-bottom flask, 4- (6-tert-butylpyridin-2-ylamino) -6-chloropyridazine-3-carboxylic acid ethyl ester (539mg, 1.61mmol) was suspended in 7M ammonia in methanol (7.87g, 10.0mL, 70.0 mmol). Sealed and stirred at room temperature for 18 hours. The solvent was evaporated and the residue dried under high vacuum to give clean 4- (6-tert-butylpyridin-2-ylamino) -6-chloropyridazine-3-carboxamide (492mg, 99.9% yield) as an off-white solid.¹H NMR(DMSO-d6):11.94(s,1H),9.23(s,1H),8.84(s,1H),8.19(s,1H),7.74(t,J＝7.9Hz,1H),7.14(d,J＝7.6Hz,1H),6.92(d,J＝7.9Hz,1H),1.34(s,9H)；LC-MS306.1,308.1[M+H]⁺.

Step 3

(3R,4R) -4- (5- (6-tert-butylpyridin-2-ylamino) -6-carbamoylpyridazin-3-ylamino) tetrahydro- 2H-pyran-3-ylcarbamic acid tert-butyl ester

To a resealable pressure tube was added 4- (6-tert-butylpyridin-2-ylamino) -6-chloropyridazine-3-carboxamide (100mg, 327. mu. mol) dissolved in NMP (2.00 mL). To this solution was added (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamic acid tert-butyl ester (70.7mg, 327. mu. mol), and the reaction mixture was heated with stirring in an oil bath at 130 ℃ for 24 hours. Additional tert-butyl (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamate (70.7mg, 327. mu. mol) was added and the reaction was continued for 24 hours. More tert-butyl (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamate (70.7mg, 327. mu. mol) was added and the reaction was continued for 72 hours. NMP was evaporated under high vacuum. The residue was purified by flash chromatography (silica gel 50 μm, 40g, Analogix), eluting with 0-5% for 20 min (containing 10% NH)₄MeOH/CH of OH₂Cl₂Tert-butyl (3R,4R) -4- (5- (6-tert-butylpyridin-2-ylamino) -6-carbamoylpyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamate (73mg, 46.0% yield) was obtained as a yellow foam.¹H NMR (chloroform-d) 11.45(br.s.,1H),8.33(s,1H),8.14(s,1H),8.06(d, J ═ 3.4Hz,1H),7.52(t, J ═ 7.9Hz,1H),6.91(d, J ═ 7.9Hz,1H),6.66(d, J ═ 7.9Hz,1H),5.65(br.s.,1H),5.37(d, J ═ 8.3Hz,1H),3.38-4.31(m,6H),1.63-2.23(m,2H),1.46(s,9H),1.39(s, 9H); LC-MS486.3[ M + H [ ]]⁺.

Step 4

6- ((3R,4R) -3-Aminotetrahydro-2H-pyran-4-ylamino) -4- (6-tert-butylpyridin-2-ylamino) pyridazin Oxazine-3-carboxamides

To (3R,4R) -4- (5- (6-tert-butylpyridin-2-ylamino) -6-carbamoylpyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamic acid tert-butyl ester(73mg, 150. mu. mol) in CH₂Cl₂To a solution in (3.00mL) was added TFA (1.48g, 1mL, 13.0mmol), and the mixture was stirred to room temperature for 18 h. The solvent was evaporated and the residue was purified by flash chromatography (spherical silica gel 20-45. mu.M, 23g, Versaflash Supelco) eluting with 0-5% over 20 minutes (containing 10% NH)₄MeOH/CH of OH₂Cl₂To give 6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (6-tert-butylpyridin-2-ylamino) pyridazine-3-carboxamide (23.5 m)_g40.5% yield) as an off-white solid.¹H NMR (chloroform-d) 11.45(s,1H),8.38(s,1H),8.03(br.s.,1H),7.54(t, J ═ 7.9Hz,1H),6.93(d, J ═ 7.6Hz,1H),6.69(d, J ═ 7.9Hz,1H),5.83(d, J ═ 8.3Hz,1H),5.37(br.s.,1H),3.91-4.13(m,2H),3.86(d, J ═ 11.0Hz,1H),3.65(d, J ═ 10.6Hz,1H),3.41-3.58(m,1H),3.04(br.s.,1H),1.97(d, J ═ 9.4, 1H), 1.63-3.85 (br.42H), 1.42H, 1H,; LC-MS386.2[ M + H [ ]]⁺.

Example 30

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-ethoxypyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

6-ethoxypyridin-2-amines

In a vial in a water bath, a 21% by weight solution of sodium ethoxide in ethanol (1.08g, 1.25mL, 15.9mmol) was diluted in ethanol (4mL) and stirred at 25 ℃ for 10 minutes, then 6-chloropyridin-2-amine (2.0g, 15.6mmol) was added in one portion. After 3 hours, the reaction mixture was transferred to a sealed flask and stirred at 130 ℃ for 18 hours. A second portion of 21% by weight sodium ethoxide in ethanol (1.08g, 1.25mL, 15.9mmol) was added and the reaction stirred at 130 ℃ for an additional 36 hours. Finally, a third portion of a 21% by weight solution of sodium ethoxide in ethanol (3.18g, 3.66mL, 46.7mmol) was added and the mixture was stirred at 140 ℃ for 6 hours and then at 130 ℃ for 18 hours. The mixture was cooled, concentrated onto silica gel, and purified by chromatography (silica gel, Analogix120g, 0-100% ethyl acetate in hexanes for 60 minutes) to give 6-ethoxypyridin-2-amine (819mg, 36%) which was used without further purification. MS (EI/CI) M/z:139[ M + H ].

Step 2

6-chloro-4- (6-ethoxypyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

In a sealed reaction tube, 6-ethoxypyridin-2-amine (775mg, 5.61mmol) and ethyl 4, 6-dichloropyridazine-3-carboxylate (620mg, 2.8mmol) were mixed with acetonitrile (14mL) and stirred at 130 ℃ for 36 hours. The mixture was cooled and concentrated to a brown solid, which was then chromatographed (80g silica cartridge, eluent 0-10% acetone in dichloromethane, 20 min, then 10% hold) to give ethyl 6-chloro-4- (6-ethoxypyridin-2-ylamino) pyridazine-3-carboxylate (40.3mg, 125 μmol, 4%) as a white solid. MS (EI/CI) M/z 323.2[ M + H ].

Step 3

6-chloro-4- (6-ethoxypyridin-2-ylamino) pyridazine-3-carboxamide

Ethyl 6-chloro-4- (6-ethoxypyridin-2-ylamino) pyridazine-3-carboxylate (40.3mg, 125. mu. mol) was dissolved in a 7N solution of ammonia in methanol (7.01g, 9mL, 63.0mmol) and stirred at 25 ℃ for 18 hours. The reaction mixture was concentrated in vacuo to give 6-chloro-4- (6-ethoxypyridin-2-ylamino) pyridazine-3-carboxamide (33mg, 112 μmol, 90%) as a pale yellow solid, which was used without purification. MS (EI/CI) M/z:294.1[ M + H ].

Step 4

(1S,2R) -2- (6-carbamoyl-5- (6-ethoxypyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylamino Benzoic acid tert-butyl ester

6-chloro-4- (6-ethoxypyridin-2-ylamino) pyridazine-3-carboxamide (33mg, 112. mu. mol) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (50mg, 233. mu. mol) were mixed in NMP (2mL) and stirred at 140 ℃ for 48 hours. A second portion of tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (50mg, 233. mu. mol) was added and the reaction stirred at 140 ℃ for 96 hours, then cooled to room temperature and concentrated in vacuo. The obtained residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc, and the organics were combined and washed with brine. The solvent was removed in vacuo to give an orange foam. The foam was concentrated onto silica gel and purified by chromatography (4g RediSep Gold, 0-5% containing 0.5% NH)₄MeOH in OH in dichloromethane, 20 min) yielded tert-butyl (1S,2R) -2- (6-carbamoyl-5- (6-ethoxypyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (32.3mg, 51.4 μmol, 46%) with some dichloromethane impurity. It was used without purification. MS (EI/CI) M/z 372.3[ M + H [ ]].

Step 5

Tert-butyl (1S,2R) -2- (6-carbamoyl-5- (6-ethoxypyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (32.2mg, 51.2. mu. mol) was dissolved in dichloromethane (1mL) andtreated with trifluoroacetic acid (744mg, 0.5mL, 6.53 mmol). The reaction was stirred at 25 ℃ for 3 hours and then concentrated in vacuo to give a brown oil. The oil was dissolved in dichloromethane, washed with 1N NaOH (3 × 5mL) and brine (5mL), and the organic phase was dried (Na)₂SO₄) Filtered and concentrated to give an off-white solid. The solid was taken up in Et₂Trituration with O (3 × 5mL) and drying in vacuo overnight afforded 6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-ethoxypyridin-2-ylamino) pyridazine-3-carboxamide as an off-white solid (12.6mg, 33.6 μmol, 66% yield).¹H NMR(DMSO-d₆):11.65(br.s.,1H),8.40(br.s.,1H),7.71(s,1H),7.64(t,J＝7.9Hz,2H),6.77(d,J＝7.8Hz,1H),6.54(d,J＝7.8Hz,1H),6.36-6.42(m,1H),4.35(q,J＝7.0Hz,2H),3.85(br.s.,1H),3.09(br.s.,1H),1.48-1.74(m,6H),1.20-1.40(m,5H)；MS(EI/CI)m/z:372.3[M+H].

Example 31

6- ((1R,2S) -2-aminocyclohexylamino) -4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

2-allyl-3-methoxy-6-nitropyridine

2-bromo-3-methoxy-6-nitropyridine (3.22g, 13.8mmol), cesium fluoride (6.3g, 41.5mmol) and tetrakis (triphenylphosphine) palladium (0) (1.6g, 1.38mmol) were mixed with 2-allyl-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (2.55g, 2.85mL, 15.2mmol) in THF (27mL) and heated at 66 deg.C for 20 hours. The mixture was cooled and then diluted with water and ethyl acetate. The phases were separated and the organic phase was washed with water (2 ×) and brine, concentrated in vacuo and then purified by chromatography (silica gel, 10-50% ethyl acetate in hexanes) to give 2-allyl-3-methoxy-6-nitropyridine (2.0g, 10.3mmol, 75%) as a blue solid. MS (EI/CI) M/z:194.8[ M + H ].

Step 2

5-methoxy-6-propylpyridin-2-amine

To a solution of 2-allyl-3-methoxy-6-nitropyridine (2.0g, 10.3mmol) in ethanol (34mL) was added 10% palladium on carbon (219mg, 2.06 mmol). The reaction was evacuated and backfilled with hydrogen. This was repeated twice more. The reaction mixture was stirred under hydrogen at 1atm for 16h, then filtered through a pad of celite and the filter cake was washed thoroughly with ethyl acetate. The filtrate was concentrated in vacuo and purified by chromatography (silica gel, 25-90% ethyl acetate in hexanes) to give 5-methoxy-6-propylpyridin-2-amine (1.41g, 8.48mmol, 82%) as an off-white solid.¹H NMR (400MHz, chloroform-d)₆)ppm7.09(d,J＝8.8Hz,1H),6.38(d,J＝8.8Hz,1H),4.28(br.s,2H),3.77(s,3H),2.68(t,J＝7.9Hz,2H),1.69(m,2H),0.99(t,J＝7.4Hz,3H)；MS(EI/CI)m/z:166.8[M+H].

Step 3

6-chloro-4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

To a solution of 4, 6-dichloropyridazine-3-carboxylic acid ethyl ester (1.9g, 8.6mmol) in acetonitrile (28.7mL) was added 5-methoxy-6-propylpyridin-2-amine (1.43g, 8.6mmol) and the mixture was heated at 70 ℃ for 72 h. The mixture was concentrated in vacuo, then purified by chromatography (silica gel, 10-60% ethyl acetate in hexanes) to give ethyl 6-chloro-4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazine-3-carboxylate (1.22g, 3.48mmol, 41%) as a yellow solid.¹H NMR (400MHz, chloroform-d)₆)ppm10.58(s,1H),8.84(s,1H),7.25(d,J＝8.7Hz,1H),6.88(d,J＝8.5Hz,1H),4.58(q,J＝7.3Hz,2H),3.88(s,3H),2.87(t,J＝7.5Hz,2H),1.84(m,2H),1.52(t,J＝7.3Hz,3H),1.05(t,J＝7.1Hz,3H)；MS(EI/CI)m/z:351.0[M+H].

Step 4

6-chloro-4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide

To a solution of ethyl 6-chloro-4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazine-3-carboxylate (1.22g, 3.48mmol) in methanol (10mL) was added a 7N solution of ammonia in methanol (23.6g, 30mL, 210mmol) and the mixture was stirred in a sealed tube at 50 ℃ for 16 h. The mixture was concentrated in vacuo to give 6-chloro-4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide (1.113g, 3.46mmol, 100%) as a yellow solid.¹H NMR(400MHz,DMSO-d₆)ppm11.72(s,1H),8.89(s,1H),8.77(s,1H),8.13(s,1H),7.47(d,J＝8.6Hz,1H),7.01(d,J＝8.6Hz,1H),3.81(s,3H),2.74(t,J＝7.3Hz,2H),1.75(m,2H),0.97(t,J＝7.3Hz,3H)；MS(EI/CI)m/z:321.9[M+H].

Step 5

(1S,2R) -2- (6-carbamoyl-5- (5-methoxy-6-propylpyridin-2-ylamino) pyridazin-3-ylamino) Cyclohexylcarbamic acid tert-butyl ester

To a solution of 6-chloro-4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide (200mg, 622. mu. mol) in NMP (2.07mL) was added tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (133mg, 622. mu. mol), and the mixture was heated at 140 ℃ for 20 hours. A second portion of tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (133mg, 622. mu. mol) was added and the mixture was stirred for a further 7 hours. The last portion of tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (133mg, 622 μmol) was added and the mixture was heated for 16 hours, then cooled, diluted with ethyl acetate and washed with brine (4 ×). The organic layers were collected, concentrated in vacuo, and the resulting residue was purified by chromatography (silica gel, 1-5% methanol in dichloromethane) to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (5-methoxy-6-propylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (96mg, 192 μmol, 31%) as a light brown solid. MS (EI/CI) M/z:500.2[ M + H ].

Step 6

6- ((1R,2S) -2-aminocyclohexylamino) -4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazin-3- Carboxamides

To a solution of tert-butyl (1S,2R) -2- (6-carbamoyl-5- (5-methoxy-6-propylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (96mg, 192 μmol) in dichloromethane (3mL) was added trifluoroacetic acid (438mg, 296 μ L, 3.84mmol), and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, then taken up with 25% aqueous NH₄OH and dichloromethane. The phases were separated and the organic phase was washed with water. The organic layer was concentrated in vacuo and then purified by chromatography (silica gel, 3-20% methanol in dichloromethane) to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide (59mg, 148 μmol, 77%) as a light brown solid.¹H NMR(400MHz,DMSO-d₆)ppm11.36(s,1H),8.30(s,1H),7.72(s,1H),7.60(s,1H),7.42(d,J＝8.8Hz,1H),6.87(d,J＝8.8Hz,1H),6.72(d,J＝7.6Hz,1H),3.96(s,1H),3.79(s,3H),3.28(s,1H),2.72(t,J＝7.3Hz,2H),1.54-1.74(m,8H),1.35(m,2H),0.94(t,J＝7.4Hz,3H)；MS(EI/CI)m/z:400.2[M+H].

Example 32

Step 1

3-methoxy-6-nitro-2- (prop-1-en-2-yl) pyridine

A mixture of 2-bromo-3-methoxy-6-nitropyridine (1.5g, 6.44mmol), 4,5, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolan (1.41g, 8.37mmol), tetrakis (triphenylphosphine) palladium (0) (744mg, 644. mu. mol), potassium phosphate (2.73g, 12.9mmol), DMA (16.1mL) and water (5.36mL) was added to a microwave bottle. The vial was sealed and heated in a microwave at 150 ℃ for 20 minutes, then cooled and diluted with ethyl acetate and brine. The organic phase was separated, washed with brine (3 ×), then concentrated in vacuo and purified by chromatography (silica gel, 5-35% ethyl acetate in hexanes) to give 3-methoxy-6-nitro-2- (prop-1-en-2-yl) pyridine (824mg, 4.24mmol, 66%) as a brown solid. MS (EI/CI) M/z:194.8[ M + H ].

Step 2

6-isopropyl-5-methoxypyridin-2-amine

To a solution of 3-methoxy-6-nitro-2- (prop-1-en-2-yl) pyridine (824mg, 4.24mmol) in ethanol (14.1mL) was added 10% palladium on carbon (45.2mg, 424. mu. mol). The reaction mixture was evacuated and backfilled with hydrogen. This was repeated twice more. The reaction was stirred under hydrogen at 1atm for 16 hours. The mixture was then filtered through a pad of celite, the filtrate was concentrated in vacuo and then purified by chromatography (silica gel, 1)0-60% ethyl acetate in hexanes) to give 6-isopropyl-5-methoxypyridin-2-amine (562mg, 3.38mmol, 80%) as a yellow solid.¹H NMR (400MHz, chloroform-d)₆)ppm7.04(d,J＝8.7Hz,1H),6.33(d,J＝8.7Hz,1H),4.12(br.s,2H),3.78(s,3H),3.36(m,1H),1.22(d,J＝7.0Hz,6H)；MS(EI/CI)m/z:166.8[M+H].

Step 3

6-chloro-4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine-3-carboxylic acid ester

To a solution of 4, 6-dichloropyridazine-3-carboxylic acid ethyl ester (747mg, 3.38mmol) in acetonitrile (11.3mL) was added 6-isopropyl-5-methoxypyridin-2-amine (562mg, 3.38mmol) and the mixture was heated to 80 ℃ for 20 h. The mixture was cooled and concentrated in vacuo. Purification by chromatography (silica gel, 10-50% ethyl acetate in hexane) afforded ethyl 6-chloro-4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine-3-carboxylate (438mg, 1.25mmol, 37%) as a yellow solid.¹H NMR (400MHz, chloroform-d)₆)ppm10.61(s,1H),9.15(s,1H),7.22(d,J＝8.7Hz,1H),6.61(d,J＝8.7Hz,1H),4.57(q,J＝7.6Hz,2H),3.88(s,3H),3.53(m,1H),1.53(t,J＝7.0Hz,3H),1.31(d,J＝6.7Hz,6H)；MS(EI/CI)m/z:351.0[M+H].

Step 4

6-chloro-4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

A mixture of ethyl 6-chloro-4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine-3-carboxylate (438mg, 1.25mmol) and a solution of ammonia in methanol (7N, 8.92mL, 62.4mmol) in methanol (1mL) was warmed at 40 ℃ for 16 h. Then in vacuumThe mixture was concentrated to give ethyl 6-chloro-4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine-3-carboxylate (438mg, 1.25mmol, 100%) as an off-white solid.¹H NMR(400MHz,DMSO-d₆)ppm11.75(s,1H),9.03(s,1H),8.78(s,1H),8.13(s,1H),7.48(d,J＝8.5Hz,1H),7.00(d,J＝8.5Hz,1H),3.82(s,3H),3.44(m,1H),1.22(d,J＝6.6Hz,6H)；MS(EI/CI)m/z:321.9[M+H].

Step 5

(1S,2R) -2- (6-carbamoyl-5- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazin-3-ylamino Yl) Cyclohexylcarbamic acid tert-butyl ester

To a solution of 6-chloro-4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine-3-carboxamide (199mg, 618. mu. mol) in NMP (2.06mL) was added tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (532mg, 2.47mmol) in four portions about every 12 hours while heating at 140 ℃. After heating for 48 hours, the mixture was cooled, diluted with ethyl acetate and brine, the phases were separated and the organic phase was washed twice more with brine. The organic phase was concentrated in vacuo and then purified by chromatography (silica gel, 1-5% methanol in dichloromethane) to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (100mg, 200 μmol, 32%) as a brown solid. MS (EI/CI) M/z 500.4[ M + H ].

Step 6

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine- 3-carboxamides

To (1S,2R) -2- (6-carbamoyl-5-, (To a solution of tert-butyl 6-isopropyl-5-methoxypyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (100mg, 200. mu. mol) in dichloromethane (3mL) was added trifluoroacetic acid (456mg, 308. mu.L, 4.00mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, then 25% aqueous NH was added₄And (4) OH solution. It was then diluted with dichloromethane and water, the phases were separated and the organic phase was washed twice with water. The organic layer was dried over anhydrous magnesium sulfate and then purified by chromatography (silica gel, 0-15% methanol in dichloromethane) to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine-3-carboxamide (43mg, 108 μmol, 54%) as an off-white solid.¹H NMR(400MHz,DMSO-d₆)ppm11.45(s,1H),8.31(s,1H),7.69(s,1H),7.58(s,1H),7.42(d,J＝8.7Hz,1H),6.85(d,J＝8.7Hz,1H),6.63(d,J＝8.0Hz,1H),3.80(s,3H),3.42(m,1H),3.15(s,1H),1.52-1.69(m,8H),1.32(m,2H),1.24(d,J＝6.4Hz,6H)；MS(EI/CI)m/z:400.3[M+H].

Example 33

4- (6- (1H-pyrazol-1-yl) pyridin-2-ylamino) -6- ((1R,2S) -2-aminocyclohexylamino) pyridazine-3-carboxamide

Step 1

6- (1H-pyrazol-1-yl) pyridin-2-amine

6- (di-Boc-amino) -2-bromopyridine (1.0g, 2.68mmol, Chronic Tech), copper (341mg, 5.36mmol), potassium hydroxide (301mg, 5.36mmol) and 1H-pyrazole (1.82g, 26.8mmol, Eq:10) were combined and stirred at 160 ℃ for 18H. The reaction mixture was cooled and diluted with EtOAc (50mL) and the solid was removed by filtration. With saturated aqueous NaHCO₃And brine, then concentrated onto silica gel and purified by chromatography (40g RediSep column, 20-1)00% ethyl acetate in hexanes for 20 min) to give 6- (1H-pyrazol-1-yl) pyridin-2-amine (365mg, 2.28mmol, 85%) as a white solid. MS (EI/CI) M/z 161.2[ M + H [ ]].

Step 2

4- (6- (1H-pyrazol-1-yl) pyridin-2-ylamino) -6-chloropyridazin-3-carboxylic acid ester

A solution of ethyl 4, 6-dichloropyridazin-3-carboxylate (230mg, 1.04mmol) and 6- (1H-pyrazol-1-yl) pyridin-2-amine (332.3mg, 2.07mmol) in acetonitrile (11.8mL) was heated in a sealed tube at 130 ℃ for 48H, then cooled, concentrated in vacuo, and purified by chromatography (silica gel, Analogix24g Redisep Gold column 0-20% acetone in dichloromethane, 20 min) to give ethyl 4- (6- (1H-pyrazol-1-yl) pyridin-2-ylamino) -6-chloropyridazin-3-carboxylate (107mg, 258. mu. mol, 25%) as a white solid. This material was-83% pure and was used in the next step without further purification. MS (EI/CI) M/z:345.1[ M + H ].

Step 3

4- (6- (1H-pyrazol-1-yl) pyridin-2-ylamino) -6-chloropyridazine-3-carboxamide

To a solution of ethyl 4- (6- (1H-pyrazol-1-yl) pyridin-2-ylamino) -6-chloropyridazine-3-carboxylate (107mg,. about.83% purity, 258 μmol) in methanol (1mL) was added a solution of ammonia in methanol (2.5mL, 17.5mmol) and the mixture was warmed at 25 ℃ for 18 hours. The mixture was cooled, filtered, and the collected solid was dried in vacuo to give 4- (6- (1H-pyrazol-1-yl) pyridin-2-ylamino) -6-chloropyridazine-3-carboxamide (45mg, 141 μmol, 55%) as a white solid.

Step 4

(1S,2R) -2- (5- (6- (1H-pyrazol-1-yl) pyridin-2-ylamino) -6-carbamoylpyridazin-3-ylamino Yl) Cyclohexylcarbamic acid tert-butyl ester

To a solution of 4- (6- (1H-pyrazol-1-yl) pyridin-2-ylamino) -6-chloropyridazine-3-carboxamide (131mg, 415. mu. mol) in NMP (5mL) was added tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (133mg, 622. mu. mol), and the mixture was stirred at 140 ℃ for 24 hours. A second portion of tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (162mg, 756. mu. mol) was added and the mixture was heated at 140 ℃ for a further 24 hours. The reaction mixture was cooled and then diluted with water. The mixture was extracted with ethyl acetate (3 × 50mL), then the combined organic phases were washed with brine (50mL), then concentrated in vacuo, and finally purified by chromatography (silica gel, 12g RediSep Gold, 2-6% 99.5:0.5 methanol: ammonium hydroxide in dichloromethane, 20 min) to give tert-butyl (1S,2R) -2- (5- (6- (1H-pyrazol-1-yl) pyridin-2-ylamino) -6-carbamoylpyridazin-3-ylamino) cyclohexylcarbamate (70mg, 142 μmol, 34%) as an off-white solid. MS (EI/CI) M/z 494.3[ M + H ].

Step 5

4- (6- (1H-pyrazol-1-yl) pyridin-2-ylamino) -6- ((1R,2S) -2-aminocyclohexylamino) pyridazin-3- Carboxamides

To a solution of tert-butyl (1S,2R) -2- (5- (6- (1H-pyrazol-1-yl) pyridin-2-ylamino) -6-carbamoylpyridazin-3-ylamino) cyclohexylcarbamate (70mg, 142. mu. mol) in dichloromethane (2.5mL) was added trifluoroacetic acid (2.01g, 1.35mL, 17.6mmol), and the mixture was stirred at 25 ℃ for 2 hours. The mixture was concentrated in vacuoThis was then diluted with dichloromethane and washed with 1n naoh (3 × 5mL) and brine (5mL) in succession. The organic phase was dried over sodium sulfate, concentrated in vacuo, and then dried in vacuo to give 4- (6- (1H-pyrazol-1-yl) pyridin-2-ylamino) -6- ((1R,2S) -2-aminocyclohexylamino) pyridazine-3-carboxamide (14.2mg, 36.1 μmol, 25%) as a white solid.¹HNMR(DMSO-d₆):11.93(s,1H),8.63-8.71(m,1H),8.45(br.s.,1H),7.78-7.94(m,3H),7.71(br.s.,1H),7.51(d,J＝7.8Hz,1H),7.05(d,J＝7.5Hz,1H),6.92(d,J＝8.0Hz,1H),6.63(dd,J＝2.5,1.8Hz,1H),4.02(br.s.,1H),3.18(br.s.,1H),1.46-1.79(m,7H),1.20-1.41(m,3H)；MS(EI/CI)m/z:394.3[M+H].

Example 34

6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

(3R,4R) -4- (6-carbamoyl-5- (6-isopropyl 677-5-methoxypyridin-2-ylamino) pyridazin-3-yl Amino) tetrahydro-2H-pyran-3-ylcarbamic acid tert-butyl ester

To a solution of 6-chloro-4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine-3-carboxamide (199mg, 618 μmol, prepared as described in example 32) in NMP (2.06mL) was added tert-butyl (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamate (536mg, 2.47mmol) in four portions about every 12 hours and the mixture was heated at 140 ℃. After a total heating time of 48 hours, the mixture was cooled and then washed with ethyl acetate and brine. The phases were separated and the organic phase was washed with brine (2 ×) and then concentrated in vacuo and the residue obtained was purified by chromatography (silica gel, 10-50% methanol in dichloromethane) to give 6-chloro-4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine-3-carboxamide (199mg, 618 μmol, quant.) as a light brown solid. MS (EI/CI) M/z 502.2[ M + H ].

Step 2

6- ((3R,4R) -3-Aminotetrahydro-2H-pyran-4-ylamino) -4- (6-isopropyl-5-methoxypyridin-2-yl) Amino) pyridazine-3-carboxamides

To a solution of tert-butyl (3R,4R) -4- (6-carbamoyl-5- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamate (86mg, 171. mu. mol) in dichloromethane (2.7mL) was added trifluoroacetic acid (391mg, 264. mu.L, 3.43mmol) and stirred at room temperature for 16H. The reaction mixture was then diluted with dichloromethane, concentrated in vacuo, and purified by chromatography (silica gel, 0-12% 99.5:0.5 methanol: NH)₄A solution of OH in dichloromethane) to give 6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (6-isopropyl-5-methoxypyridin-2-ylamino) pyridazine-3-carboxamide (51mg, 127 μmol, 74%) as a yellow solid.¹H NMR (400MHz, methanol-d)₆)ppm8.08(s,1H),7.42(d,J＝8.6Hz,1H),6.91(d,J＝8.9Hz,1H),4.35(m,1H),4.12(dd,J＝12.1,3.4Hz,1H),4.07(d,J＝12.6Hz,1H),3.89(s,1H),3.88(s,3H),3.80(d,J＝12.8Hz,1H),3.65(m,1H),3.52(m,1H),2.12(m,1H),1.96(d,J＝13.1Hz,1H),1.32(d,J＝5.8Hz,6H)；MS(EI/CI)m/z:402.3[M+H].

Example 35

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-isopropyl-4-methylpyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

6-chloro-4- (6-isopropyl-4-methylpyridin-2-ylamino) pyridazine-3-carboxylic acid ester

To a solution of ethyl 4, 6-dichloropyridazine-3-carboxylate (260mg, 1.18mmol) in acetonitrile (3.9mL) was added 6-isopropyl-4-methylpyridin-2-amine (265mg, 1.76mmol), and the mixture was heated at 140 ℃ for 48 hours. The mixture was cooled, concentrated in vacuo, and then purified by chromatography (silica gel, 5-30% ethyl acetate in hexanes) to give ethyl 6-chloro-4- (6-isopropyl-4-methylpyridin-2-ylamino) pyridazine-3-carboxylate (117mg, 349 μmol, 30%) as an off-white solid.¹H NMR (400MHz, chloroform-d)₆)ppm10.60(s,1H),9.39(s,1H),6.76(s,1H),6.59(s,1H),4.58(q,J＝7.0Hz,2H),3.04(m,1H),2.35(s,3H),1.53(t,J＝7.1Hz,3H),1.35(d,J＝7.0Hz,6H),；MS(EI/CI)m/z:335.0[M+H].

Step 2

6-chloro-4- (6-isopropyl-4-methylpyridin-2-ylamino) pyridazine-3-carboxamide

To a solution of ethyl 6-chloro-4- (6-isopropyl-4-methylpyridin-2-ylamino) pyridazine-3-carboxylate (115mg, 343. mu. mol) in methanol (1mL) was added a methanol solution of ammonia (7N, 4.91mL, 34.3mmol), and the mixture was heated at 45 ℃ for 20 hours. The mixture was concentrated in vacuo to give 6-chloro-4- (6-isopropyl-4-methylpyridin-2-ylamino) pyridazine-3-carboxamide (105mg, 343 μmol, 100%) as a white solid.¹H NMR(400MHz,DMSO-d₆)ppm11.91(s,1H),9.25(s,1H),8.85(s,1H),8.21(s,1H),6.87(s,1H),6.77(s,1H),3.01(m,1H),2.31(s,3H),1.28(d,J＝6.6Hz,6H)；MS(EI/CI)m/z:305.9[M+H].

Step 3

(1S,2R) -2- (6-carbamoyl-5- (6-isopropyl-4-methylpyridin-2-ylamino) pyridazin-3-ylamino) Cyclohexylcarbamic acid tert-butyl ester

To a stirred solution of 6-chloro-4- (6-isopropyl-4-methylpyridin-2-ylamino) pyridazine-3-carboxamide (54mg, 177 μmol) in NMP (590 μ L) was added tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (227.1mg, 883 μmol) in three portions every 12 hours while heating the mixture at 140 deg.C (during the period between additions). After a total of 36 hours, the mixture was cooled and then diluted with ethyl acetate and water. The organic phase was separated and then washed with water and brine. The organic phase was concentrated in vacuo and finally purified by chromatography (silica gel, 30-80% ethyl acetate in hexanes) to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (6-isopropyl-4-methylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (35mg, 72.4. mu. mol, 41.0%) as a brown oil. MS (EI/CI) M/z 484.3[ M + H ].

Step 4

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6-isopropyl-4-methylpyridin-2-ylamino) pyridazin-3- Carboxamides

To a solution of tert-butyl (1S,2R) -2- (6-carbamoyl-5- (6-isopropyl-4-methylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (35mg, 72.4. mu. mol) in dichloromethane (1.1mL) was added trifluoroacetic acid (165mg, 112. mu.L, 1.45mmol), and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated in vacuo, then the residue was diluted with dichloromethane and a few drops of 25% aqueous NH were added₄OH until the pH of the mixture is measured to 8. The mixture was then washed with water, the organic phase was collected, concentrated in vacuo and finally purified by chromatography (silica gel, 3-10% 99.5:0.5 methanol: NH)₄Dichloromethane solution of OH) to give 6- ((1R,2S) -2-aminocyclHexylamino) -4- (6-isopropyl-4-methylpyridin-2-ylamino) pyridazine-3-carboxamide (15mg, 39.1. mu. mol, 54%) as a light brown solid.¹H NMR(400MHz,DMSO-d₆)ppm11.64(s,1H),8.36(s,1H),8.07(s,1H),7.64(s,1H),6.79(d,J＝4.3Hz,1H),6.73(s,1H),6.60(s,1H),3.90(s,1H),2.98(m,1H),2.27(s,3H),1.52-1.76(m,6H),1.38(m,2H),1.27(d,J＝7.0Hz,6H)；MS(EI/CI)m/z:384.1[M+H].

Example 36

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

2- (6-Bromopyridin-2-yl) -2-methylpropanenitrile

To a dry 500mL round bottom flask was added a solution of isobutyronitrile (3.29g, 4.27mL, 47.6mmol) in toluene (100mL), then the solution was cooled to 0 ℃ and a solution of khmds0.5m in toluene (100mL, 50.0mmol) was slowly added. After complete addition, the reaction mixture was warmed to room temperature over 1 hour. The resulting mixture was added to a solution of 2, 6-dibromopyridine (28.2g, 119mmol, available from Aldrich) in toluene (100 mL). The pale yellow solution quickly turned a deep red color while adding. The reaction mixture was stirred at room temperature for 18 hours. The crude mixture was diluted with ether and washed with saturated aqueous ammonium chloride and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The semi-solid residue was suspended in a small amount of toluene and filtered off, and the light brown solid corresponding to 2, 6-dibromopyridine was recovered. The filtrate was purified by flash chromatography (silica gel, 50 μm, 220g, Redflash Teledyne-Isco) eluting with 0-50% dichloromethane/hexanes over 20 minutes to give 2- (6-bromopyridin-2-yl) -2-methylpropanenitrile (7.608g, 28.4% yield) as a pale yellow oil which solidified upon standingAnd turned into a white solid.¹H NMR (chloroform-d) 7.58-7.61(m,2H),7.42-7.46(m,1H),1.76(s, 6H); LC-MS225.0226.9[ M + H [ ]]⁺.

Step 2

2- (6-Aminopyridin-2-yl) -2-methylpropanenitrile

To a thick-walled resealable tube was charged copper (I) oxide (159mg, 1.11mmol), 2- (6-bromopyridin-2-yl) -2-methylpropanenitrile (5000mg, 22.2mmol), 28% ammonium hydroxide solution (26.9mL, 444mmol), and K under argon₂CO₃(614mg, 4.44mmol), N-dimethylethylenediamine (196mg, 244. mu.l, 2.22mmol), and ethylene glycol (44.4 mL). The reaction was heated to 60 ℃ with stirring for 6 hours. After cooling, the reaction mixture was extracted with dichloromethane (3 × 25mL), and the combined organics were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (silica gel, 50 μm, 40g, Analogix) eluting with 0-5% (10% ammonium hydroxide in methanol) in dichloromethane over 20 minutes to give 2- (6-aminopyridin-2-yl) -2-methylpropanenitrile (3.2g, 89.4% yield) as a white solid.¹H NMR (chloroform-d) 7.34 to 7.46(m,1H),6.81(d, J ═ 7.2Hz,1H),6.40(d, J ═ 7.9Hz,1H),4.67(br.s.,2H),1.63 to 1.68(m, 6H); LC-MS162.1[ M + H [ ]]⁺.

Step 3

6-chloro-4- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

A mixture of ethyl 4, 6-dichloropyridazine-3-carboxylate (1.4g, 6.33mmol) and 2- (6-aminopyridin-2-yl) -2-methylpropanenitrile (2.04g, 12.7mmol) was dissolved in acetonitrile (3.00mL) and heated to 130 ℃ for 18 h. Cooling the mixtureHowever, concentrate, adsorb the residue onto silica gel and purify by flash chromatography (silica gel, 45 μ M, 160g, Thomson), eluting with 0-20% acetone in dichloromethane over 20 minutes, isolate the impure desired mixture, concentrate all fractions containing the desired product, and dissolve the residue in dichloromethane, evaporate at least the volume, where a solid precipitates, filters and dries to give the desired ethyl 6-chloro-4- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazine-3-carboxylate (792mg, 36.2% yield).¹H NMR (chloroform-d): 10.86(s,1H),9.27(s,1H),7.75(t, J ═ 7.9Hz,1H),7.26(d, J ═ 7.9Hz,1H),6.90(d, J ═ 7.9Hz,1H),4.58(q, J ═ 7.2Hz,2H),1.81(s,6H),1.52(t, J ═ 7.2Hz, 3H); LC-MS346.1[ M + H [ ]]⁺.

Step 4

6-chloro-4- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazine-3-carboxamide

In a 50mL round-bottom flask, ethyl 6-chloro-4- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazine-3-carboxylate (792mg, 2.29mmol) was suspended in a 7M solution of ammonia in methanol (7.87g, 10.0mL, 70.0 mmol). Sealed and stirred at room temperature for 18 hours. The bulk of the solid formed during the reaction was isolated by filtration, the filter cake was rinsed with fresh methanol and dried under high vacuum to give clean 6-chloro-4- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazine-3-carboxamide (581mg, 80.1% yield) as an off-white solid.¹H NMR(DMSO-d₆):12.14(s,1H),9.22(s,1H),8.89(s,1H),8.23(s,1H),7.87(t,J＝7.9Hz,1H),7.27(d,J＝7.6Hz,1H),7.10(d,J＝7.9Hz,1H),1.73(s,6H)；LC-MS316.9[M+H]⁺.

Step 5

(1S,2R) -2- (6-carbamoyl-5- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazin-3-ylamino Yl) Cyclohexylcarbamic acid tert-butyl ester

To a resealable pressure tube were added 6-chloro-4- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazine-3-carboxamide (200mg, 631. mu. mol) and tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (135mg, 631. mu. mol) in NMP (2.00 mL). The reaction mixture was heated with stirring in an oil bath at 120 ℃ for 18 hours. More tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (135mg, 631. mu. mol) was then added in small portions over 7 hours and the reaction was continued for 18 hours. The solvent was distilled off under high vacuum. The residue was dissolved in dichloromethane containing a few drops of methanol and then purified by flash column (spherical silica gel 20-45. mu.M, 50g, Versaflash Supelco) using 0-5% (containing 10% NH)₄MeOH/CH of OH₂Cl₂Elution was carried out for 20 minutes to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (110mg, 222. mu. mol, 35.2% yield) as a yellow foam.¹H NMR (chloroform-d) 11.48(s,1H),8.82(br.s.,1H),8.00-8.11(m,1H),7.62(t, J ═ 7.9Hz,1H),6.89(d, J ═ 7.6Hz,1H),6.79(d, J ═ 8.3Hz,1H),5.53-5.85(m,2H),5.06(d, J ═ 8.3Hz,1H),4.47(br.s.,1H),3.80-3.99(m,1H),1.24-1.93(m, 23H); LC-MS495.1[ M + H [ ]]⁺.

Some starting material 6-chloro-4- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazine-3-carboxamide was also recovered (130mg, 65.0% yield).

Step 6

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazine- 3-carboxamides

To (1S,2R) -2- (6-carbamoyl-5- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazine-3-ylamino) cyclohexyl carbamic acid tert-butyl ester (110mg, 222. mu. mol) in CH₂Cl₂To a solution in (3.00mL) was added TFA (1.48g, 1.00mL, 13.0mmol), and the reaction mixture was stirred to room temperature for 18 hours. The solvent was evaporated and the residue purified by flash column (spherical silica gel 20-45. mu.M, 23g, Versaflash Supelco) using 0-5% (containing 10% NH)₄MeOH/CH of OH₂Cl₂Elution took 20 minutes to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (6- (2-cyanoprop-2-yl) pyridin-2-ylamino) pyridazine-3-carboxamide (50mg, 57% yield) as an off-white solid.¹H NMR (chloroform-d) 11.47(s,1H),8.76(s,1H),8.06(d, J ═ 3.0Hz,1H),7.60(t, J ═ 7.9Hz,1H),6.86(d, J ═ 7.6Hz,1H),6.78(d, J ═ 7.9Hz,1H),5.60-5.77(m,2H),4.25(br.s.,1H),3.11-3.24(m,1H),1.32-1.92(m, 16H); LC-MS395.1[ M + H [ ]]⁺.

Example 37

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

2- (6-Bromopyridin-2-yl) propan-2-ol

To a dry 250mL round bottom flask equipped with a stir bar and a septum (septum) was added a 1.6M solution of n-butyllithium in hexane (30.3mL, 48.5mmol), the flask was cooled to-76 ℃ in a dry ice-acetone bath and THF (30mL) was added to the solution, then a solution of 2, 6-dibromopyridine (11.5g, 48.5mmol) in THF (60mL) was slowly added over a 15 minute cannula. The dark yellow-brown solution was stirred in a dry ice bath for 30 minutes, then propan-2-one (4.75g, 6mL, 81.7mmol) was added. The dark green solution was stirred in a dry ice bath for 15 minutes and then warmed to room temperature. After 1 hour, saturated aqueous ammonium chloride (100mL) was carefully added, and the product wasExtraction with dichloromethane (3 × 200) and the combined organics were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (silica gel, 50 μm, 150g, Analogix) eluting with 0-50% dichloromethane/hexanes over 20 minutes to give 2- (6-bromopyridin-2-yl) propan-2-ol (9.9g, 94.3% yield) as a light yellow clear liquid.¹H NMR (chloroform-d) 7.52-7.59(m,1H),7.33-7.40(m,2H),4.05(br.s.,1H),1.55(s, 6H); LC-MS216.1,218.1[ M + H [ ]]⁺.

Step 2

2- (6-Aminopyridin-2-yl) propan-2-ol

To a thick-walled resealable tube under argon atmosphere was charged copper (I) oxide (53.0mg, 370. mu. mol), 2- (6-bromopyridin-2-yl) propan-2-ol (1600mg, 7.4mmol), 28% ammonium hydroxide solution (16.5M) (8.98mL, 148mmol), K₂CO₃(205mg, 1.48mmol), N-dimethylethylenediamine (65.3mg, 81.3. mu.l, 740. mu. mol), and ethylene glycol (14.8 mL). The reaction was stirred at 60 ℃ for 6 hours. After cooling to room temperature, the reaction mixture was extracted with dichloromethane (3 × 25mL), and the combined organics were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (spherical silica gel 20-45 μ M,23 g, VersaflashSupelco) eluting with 0-5% (10% ammonium hydroxide in methanol) in dichloromethane over 20 minutes to give 2- (6-aminopyridin-2-yl) propan-2-ol (626mg, 55.5% yield) as a light yellow liquid.¹H NMR (chloroform-d): 7.44(t, J ═ 7.7Hz,1H),6.67(d, J ═ 7.6Hz,1H),6.38(d, J ═ 7.9Hz,1H),5.12(s,1H),4.38 to 4.55(m,2H),1.49(s, 6H); LC-MS153.1,155.1[ M + H [ ]]⁺.

Step 3

6-chloro-4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

A mixture of ethyl 4, 6-dichloropyridazine-3-carboxylate (0.45g, 2.04mmol) and 2- (6-aminopyridin-2-yl) propan-2-ol (620mg, 4.07mmol) was dissolved in acetonitrile (3.00mL) and heated at 130 ℃ for 18 h. The mixture was cooled, concentrated, and the residue was adsorbed onto silica gel and purified by flash chromatography (silica gel, 45 μ M, 160g, Thomson) eluting with 0-100% hexane/ethyl acetate over 40 minutes to give ethyl 6-chloro-4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) pyridazine-3-carboxylate (405mg, 59.1% yield).¹H NMR (chloroform-d) 10.72(s,1H),9.00(s,1H),7.76(t, J ═ 7.9Hz,1H),7.34(d, J ═ 7.9Hz,1H),6.89(d, J ═ 7.9Hz,1H),5.21(br.s.,1H),4.60(q, J ═ 7.2Hz,2H),1.67(s,6H),1.54(t, J ═ 7.9Hz, 3H); LC-MS337.0,339.0[ M + H [ ]]⁺.

Step 4

6-chloro-4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) pyridazine-3-carboxamide

In a 50mL round-bottom flask, ethyl 6-chloro-4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) pyridazine-3-carboxylate (792mg, 2.35mmol) was suspended in a 7M solution of ammonia in methanol (7.87g, 10.0mL, 70.0 mmol). Sealed and stirred at room temperature for 5 hours. The solvent was evaporated and the residue was purified by flash chromatography (spherical silica gel 20-45. mu.M, 50g, VersaflashSupelco) using 0-5% (containing 10% NH)₄MeOH/CH of OH₂Cl₂Elution was carried out for 20 min to give 6-chloro-4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) pyridazine-3-carboxamide (241mg, 33.3% yield) as an off-white solid.¹HNMR (chloroform-d): 11.64(s,1H),8.96(s,1H),8.18(br.s.,1H),7.71(t, J ═ 7.9Hz,1H),7.25(d, J ═ 7.6Hz,1H),6.86(d, J ═ 8.3Hz,1H),5.70(br.s.,1H),1.64(s, 6H); LC-MS308.0,310.0[ M + H [ ]]⁺.

Step 5

(1S,2R) -2- (6-carbamoyl-5- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) pyridazin-3-ylamino Yl) Cyclohexylcarbamic acid tert-butyl ester

To a dry 50mL round bottom flask was added 6-chloro-4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) pyridazine-3-carboxamide (241mg, 783. mu. mol) dissolved in NMP (2.00 mL). To the solution was added tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (168mg, 783. mu. mol), and the reaction mixture was heated with stirring in an oil bath at 120 ℃ for 18 hours. Thereafter, more tert-butyl (1S,2R) -2-aminocyclohexylcarbamate (168mg, 783. mu. mol) was added in small portions over the course of 7 hours. After the last addition, the reaction was continued for 18 hours. After cooling to room temperature, the solvent is evaporated off under high vacuum, the residue is dissolved in dichloromethane containing a few drops of methanol and then purified by flash chromatography (spherical silica gel 20-45. mu.M, 50g, Versaflash Supelco) using 0-5% (containing 10% NH)₄MeOH/CH of OH₂Cl₂Elution was carried out for 20 minutes to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (179mg, 47.1% yield) as a yellow foam.¹H NMR (chloroform-d) 11.54(br.s.,1H),8.16(br.s.,1H),8.04(s,1H),7.60(t, J ═ 7.9Hz,1H),7.05(d, J ═ 7.6Hz,1H),6.76(d, J ═ 8.3Hz,1H),6.53-6.70(m,1H),5.81(d, J ═ 3.4Hz,1H),5.43(br.s.,1H),3.71-4.14(m,3H),1.23-1.90(m, 23H); LC-MS486.2[ M + H [ ]]⁺.

Step 6

6- ((1R,2S) -2-aminocyclohexylamino) -4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) pyridazine- 3-carboxamides

To (1S,2R) -tert-butyl (6-carbamoyl-5- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (179mg, 369. mu. mol) in CH₂Cl₂To a solution in (3.00mL) was added TFA (1.48g, 1.00mL, 13.0mmol), and the mixture was stirred to room temperature for 18 h. The solvent was evaporated and the residue was purified by flash chromatography (spherical silica gel 20-45. mu.M, 23g, Versaflash Supelco) using 0-5% (containing 10% NH)₄MeOH/CH of OH₂Cl₂Elution was carried out for 20 min to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (6- (2-hydroxypropan-2-yl) pyridin-2-ylamino) pyridazine-3-carboxamide (80mg, 56.3% yield) as an off-white foam.¹H NMR(DMSO-d₆):11.76(s,1H),8.38(br.s.,1H),7.90(s,1H),7.60-7.78(m,2H),7.23(d,J＝7.6Hz,1H),6.70-6.83(m,2H),5.18(s,1H),3.70(br.s.,1H),3.09(br.s.,1H),1.21-1.77(m,16H)；LC-MS386.1[M+H]⁺.

Example 38

6- ((1R,2S) -2-aminocyclohexylamino) -4- (4-methyl-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

(E) -4-methyl-6- (prop-1-enyl) pyridin-2-amine

6-bromo-4-methylpyridin-2-amine (500mg, 2.67mmol), (E) -6-methyl-2- (prop-1-enyl) -1,3,6, 2-dioxazaborolan (dioxazaborocan) -4, 8-dione (1.05g, 5.35mmol), cesium carbonate (2.61g, 8.02mmol) and tetrakis (triphenylphosphine) palladium (0) (309mg, 267. mu. mol) were mixed with dioxane (7.4mL) and water (1.5mL) and the mixture was heated to 150 ℃ in a microwave for 60 minutes. The reaction mixture was cooled and then diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with water and brine. The organic phase was concentrated in vacuo and then purified by chromatography (silica gel, 20% -60% ethyl acetate in hexane) to give a residue which was triturated with methanol to give a yellow precipitate. The precipitate was collected by filtration and dried to give (E) -4-methyl-6- (prop-1-enyl) pyridin-2-amine (235mg, 1.59mmol, 59%) as a yellow oil. MS (EI/CI) M/z:148.8[ M + H ].

Step 2

4-methyl-6-propylpyridin-2-amine

To a solution of (E) -4-methyl-6- (prop-1-enyl) pyridin-2-amine (235mg, 1.59mmol) in ethanol (5.29mL) was added 10% palladium on carbon (169mg, 159. mu. mol). The reaction mixture was evacuated and backfilled with H₂Three times. The mixture was stirred under hydrogen atmosphere (balloon, 1atm) for 16 hours, and then filtered through a pad of celite. The filtrate was collected, concentrated in vacuo, and purified by chromatography (silica gel, 30-60% ethyl acetate in hexanes, gradient) to give 4-methyl-6-propylpyridin-2-amine (135mg, 899 μmol, 57%) as a colorless oil. MS (EI/CI) M/z 150.8[ M + H ]].

Step 3

6-chloro-4- (4-methyl-6-propylpyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

To a solution of 4, 6-dichloropyridazine-3-carboxylic acid ethyl ester (335mg, 1.52mmol) in acetonitrile (5mL) was added 4-methyl-6-propylpyridin-2-amine (342mg, 2.27mmol) and the mixture was heated at 130 ℃ in a sealed tube for 72 h. The mixture was cooled, concentrated in vacuo, and then purified by chromatography (silica gel, 10-35% ethyl acetate in hexanes) to give 6-chloro-4- (4-methyl-6-propylpyridin-2-ylamino) pyridazinEthyl oxazine-3-carboxylate (147mg, 439. mu. mol, 29%) as a light brown solid.¹H NMR (400MHz, chloroform-d)₆)ppm10.61(s,1H),9.26(s,1H),6.74(s,1H),6.61(s,1H),4.58(q,J＝7.1Hz,2H),2.76(t,J＝7.5Hz,1H),2.35(s,3H),1.84(m,2H),1.53(t,J＝6.9Hz,3H),1.03(t,J＝7.3Hz,3H),；MS(EI/CI)m/z:335.0[M+H].

Step 4

6-chloro-4- (4-methyl-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide

A mixture of ethyl 6-chloro-4- (4-methyl-6-propylpyridin-2-ylamino) pyridazine-3-carboxylate (147mg, 439. mu. mol) in methanol solution of ammonia (7N, 6.27mL, 43.9mmol) was heated to 40 ℃ for 16 h. The mixture was concentrated in vacuo to give 6-chloro-4- (4-methyl-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide (134mg, 438 μmol, 100%) as a white solid.¹H NMR(400MHz,DMSO-d₆)ppm11.88(s,1H),9.16(s,1H),8.82(s,1H),8.18(s,1H),6.83(s,1H),6.76(s,1H),2.69(t,J＝7.3Hz,2H),2.29(s,3H),1.76(m,1H),0.95(t,J＝7.3Hz,3H)；MS(EI/CI)m/z:305.9[M+H].

Step 5

(1S,2R) -2- (6-carbamoyl-5- (4-methyl-6-propylpyridin-2-ylamino) pyridazin-3-ylamino) cyclic Hexyl carbamic acid tert-butyl ester

Over a period of 36 hours, (1S,2R) -tert-butyl 2-aminocyclohexylcarbamate (376mg, 1.75mmol) was added in 3 portions approximately every 12 hours to a solution of 6-chloro-4- (4-methyl-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide (134mg, 438 μmol) in NMP (1.5mL) and heated at 140 ℃ during the addition. The mixture was then diluted with ethyl acetate and brine. The phases were separated and the organic phase was washed twice with brine. The organic phase was concentrated in vacuo, then purified by chromatography (silica gel, 30-100% ethyl acetate in hexanes) to give tert-butyl (1S,2R) -2- (6-carbamoyl-5- (4-methyl-6-propylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (91mg, 188 μmol, 43%) as a light brown solid. MS (EI/CI) M/z 484.3[ M + H ].

Step 6

6- ((1R,2S) -2-Aminocyclohexylamino) -4- (4-methyl-6-propylpyridin-2-ylamino) pyridazin-3-carboxylic acid methyl ester Amides of carboxylic acids

To a solution of tert-butyl (1S,2R) -2- (6-carbamoyl-5- (4-methyl-6-propylpyridin-2-ylamino) pyridazin-3-ylamino) cyclohexylcarbamate (91mg, 188 μmol) in dichloromethane (2.9mL) was added trifluoroacetic acid (429mg, 290 μ L, 3.76mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and then diluted with NH₄OH and dichloromethane. The mixture was washed with water, then the organic phase was concentrated in vacuo and purified by chromatography (silica gel, 3-15% methanol in dichloromethane) to give 6- ((1R,2S) -2-aminocyclohexylamino) -4- (4-methyl-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide (46mg, 120 μmol, 64%) as an off-white solid.¹H NMR(400MHz,DMSO-d₆)ppm11.59(s,1H),8.34(s,1H),8.08(s,1H),7.63(s,1H),6.80(d,J＝7.2Hz,1H),6.70(s,1H),6.60(s,1H),3.88(s,1H),3.25(s,1H),2.67(t,J＝7.4Hz,1H),2.26(s,3H),1.71(m,2H),1.54-1.71(m,6H),1.35(s,2H),0.93(t,J＝7.2Hz,3H)；MS(EI/CI)m/z:384.1[M+H].

Example 39

6- ((3R,4R) -3-Aminotetrahydro-2H-pyran-4-ylamino) -4- (4-methyl-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

(3R,4R) -4- (6-carbamoyl-5- (4-methyl-6-propylpyridin-2-ylamino) pyridazin-3-ylamino) tetrakis hydro-2H-pyran-3-ylcarbamic acid tert-butyl ester

Over a period of 48 hours, (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamic acid tert-butyl ester (206.4mg, 956. mu. mol) was added in four portions approximately every 12 hours to a solution of 6-chloro-4- (4-methyl-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide (73mg, 239. mu. mol, prepared as described in example 38) in NMP (796. mu.L) and heated at 140 ℃ during the addition. After 48 hours, the mixture was diluted with ethyl acetate and brine. The phases were separated and the organic phase was washed with brine (3 ×), concentrated in vacuo and purified by chromatography (silica gel, 1-5% methanol in dichloromethane) to give tert-butyl (3R,4R) -4- (6-carbamoyl-5- (4-methyl-6-propylpyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamate (27mg, 56 μmol, 23%) as a light brown solid. MS (EI/CI) M/z 486.2[ M + H ].

Step 2

6- ((3R,4R) -3-Aminotetrahydro-2H-pyran-4-ylamino) -4- (4-methyl-6-propylpyridin-2-ylamino) Yl) pyridazine-3-carboxamides

To a solution of tert-butyl (3R,4R) -4- (6-carbamoyl-5- (4-methyl-6-propylpyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamate (27mg, 55.6. mu. mol) in dichloromethane (1mL) was added trifluoroacetic acid (127mg, 85.7. mu.L, 1.11mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, then dichloromethane and 25% waterSex NH₄The residue was diluted with OH. The mixture was washed with water (2 ×), then the organic phase was collected, concentrated in vacuo, and purified by chromatography (silica gel, 1-10% 99.5:0.5 methanol: NH)₄A solution of OH in dichloromethane) to give 6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (4-methyl-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide (7mg, 18.2 μmol, 33%) as an off-white solid.¹H NMR(400MHz,DMSO-d₆)ppm11.61(s,1H),8.38(s,1H),8.10(s,1H),7.68(s,1H),6.98(d,J＝5.8Hz,1H),6.71(s,1H),6.61(s,1H),4.08(q,J＝5.5Hz,1H),3.92(d,J＝9.9Hz,1H),3.81(d,J＝12.2Hz,1H),3.59(d,J＝11.7Hz,1H),3.47(t,J＝11.8Hz,1H),3.28(s,1H),3.17(d,J＝5.0Hz,2H),2.67(t,J＝7.8Hz,1H),2.33(s,1H),2.26(s,3H),1.72(m,3H),1.23(s,1H),0.93(t,J＝7.4Hz,3H)；MS(EI/CI)m/z:386.2[M+H].

Example 40

6- ((3R,4R) -3-Aminotetrahydro-2H-pyran-4-ylamino) -4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

(3R,4R) -4- (6-carbamoyl-5- (5-methoxy-6-propylpyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamic acid tert-butyl ester

To a solution of 6-chloro-4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide (200mg, 622 μmol, prepared as described in example 31) in NMP (2.1mL) was added tert-butyl (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamate (402mg, 1.86mmol) in 3 portions about every 12 hours and heated to 140 ℃ during the addition. After a total of 36 hours, the mixture was cooled, diluted with ethyl acetate and brine, then the organic phase was separated and washed with brine (3 ×). The organic phase was then concentrated in vacuo and the resulting residue was purified by chromatography (silica gel, 1-5% methanol in dichloromethane) to give tert-butyl (3R,4R) -4- (6-carbamoyl-5- (5-methoxy-6-propylpyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamate (77mg, 154 μmol, 25%) as a light brown solid. MS (EI/CI) M/z 502.2[ M + H ].

Step 2

6- ((3R,4R) -3-Aminotetrahydro-2H-pyran-4-ylamino) -4- (5-methoxy-6-propylpyridin-2-ylamino) Yl) pyridazine-3-carboxamides

To a solution of tert-butyl (3R,4R) -4- (6-carbamoyl-5- (5-methoxy-6-propylpyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamate (77mg, 154 μmol) in dichloromethane (2.4mL) was added trifluoroacetic acid (350mg, 237 μ L, 3.07mmol), and the mixture was stirred at room temperature. After 16h, the mixture was concentrated in vacuo and then taken up with 25% aqueous NH₄OH and dichloromethane. The mixture was washed with water, then the organic phase was concentrated in vacuo and purified by chromatography (silica gel, 3-10% methanol in dichloromethane) to give 6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (5-methoxy-6-propylpyridin-2-ylamino) pyridazine-3-carboxamide (33mg, 82.2 μmol, 54%) as an off-white solid.¹H NMR(400MHz,DMSO-d₆)ppm11.37(s,1H),8.33(s,1H),7.74(s,1H),7.58(s,1H),7.41(d,J＝8.7Hz,1H),6.87(d,J＝8.8Hz,1H),6.76(d,J＝7.6Hz,1H),3.98(br.s,1H),3.84(m,1H),3.79(s,3H),3.70(d,J＝11.3Hz,1H),3.51(d,J＝11.5Hz,1H),3.40(t,J＝11.2Hz,1H),2.99(s,1H),2.72(t,J＝7.4Hz,2H),1.81(m,1H),1.72(m,2H),1.72(m,3H),0.94(t,J＝7.3Hz,3H)；MS(EI/CI)m/z:402.2[M+H].

EXAMPLE 41

6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (5-fluoro-6-isopropylpyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

(6-bromo-5-fluoro-pyridin-2-yl) -carbamic acid tert-butyl ester

To a solution of 6-bromo-5-fluoro-2-pyridinecarboxylic acid (2g, 9.09mmol) in tert-butanol (46mL) and triethylamine (1.27mL, 9.09mmol, Eq:1.00) was added DPPA (1.97mL, 9.09 mmol). The slurry was stirred at room temperature until all solids dissolved (-15 minutes), after which it was heated to 85 ℃ for 2 hours. After cooling, the mixture was concentrated onto silica gel and chromatographed (silica gel, 5% -30% EtOAc in hexanes) to give slightly impure (6-bromo-5-fluoro-pyridin-2-yl) -carbamic acid tert-butyl ester (1.55g, 59%).¹H NMR (400MHz, chloroform-d)₆)ppm7.97(d,J＝8.6Hz,1H),7.43(d,J＝8.6Hz,1H),1.53(s,9H).

Step 2

6-bromo-5-fluoro-pyridin-2-ylamine

To a solution of (6-bromo-5-fluoro-pyridin-2-yl) -carbamic acid tert-butyl ester (1.43g, 4.91 mmol) in DCM (25mL) was added TFA (3.78mL, 49.1mmol, Eq: 10.0). The mixture was stirred at rt for 2h, then concentrated in vacuo and redissolved in EtOAc. Sequentially using saturated aqueous NaHCO₃The organic layer was washed with water and brine. The resulting organic layer was concentrated onto silica gel and chromatographed (10% -40% EtOAc/hexanes) to give 6-bromo-5-fluoro-pyridin-2-ylamine (850mg, 91%).¹H NMR (400MHz, chloroform-d)₆)ppm7.23(dd,J＝8.6,7.5Hz,1H),6.41(dd,J＝8.6,2.6Hz,1H),4.40(br.s,2H).

Step 3

5-fluoro-6-isopropenyl-pyridin-2-ylamine

To a solution of 6-bromo-5-fluoro-pyridin-2-ylamine (850mg, 4.45mmol) in dimethylacetamide (13.5mL) was added 4,4,5, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolan (1.09mL, 5.79mmol), tetrakis (triphenylphosphine) palladium (514mg, 445. mu. mol) and potassium phosphate (1.89g, 8.9mmol) in water (4mL, 223 mmol). The mixture was sealed in a microwave bottle and heated in the microwave at 150 ℃ for 15 minutes. After cooling, the mixture was diluted with EtOAc, washed with water and brine, concentrated onto silica gel, and chromatographed (20% -100% EtOAc in hexanes) to give 5-fluoro-6-isopropenyl-pyridin-2-ylamine, contaminated with catalyst-derived impurities (-800 mg), which was used in the next step without further purification.

Step 4

5-fluoro-6-isopropylpyridin-2-amine

To a solution of 5-fluoro-6-isopropenyl-pyridin-2-ylamine (crude from the previous step, 4.45mmol) in methanol (13.5mL) was added 10% palladium on carbon (95mg) at room temperature. A hydrogen balloon (1atm) was attached and the mixture was stirred overnight. After 18 h, the mixture was filtered through celite, concentrated onto silica gel, and chromatographed (10% -40% EtOAc in hexanes) to give 5-fluoro-6-isopropylpyridin-2-amine (470mg, 69%, two steps).¹H NMR (400MHz, chloroform-d)₆)ppm7.12(t,J＝9.2Hz,1H),6.30(dd,J＝8.5,3.0Hz,1H),4.31(br.s,2H),4.15(m,1H),1.26(d,J＝7.2Hz,6H).

Step 5

6-chloro-4- (5-fluoro-6-Isopropylpyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

To a solution of 4, 6-dichloropyridazine-3-carboxylic acid ethyl ester (674mg, 3.05mmol) in acetonitrile (10mL) was added 5-fluoro-6-isopropylpyridin-2-amine (470mg, 3.05mmol) and heated at 130 ℃ for 18 h in a sealed tube. After completion, the mixture was concentrated onto silica gel and purified by chromatography (silica gel, 10% -33% EtOAc in hexanes) to give recovered aniline (300mg) and ethyl 6-chloro-4- (5-fluoro-6-isopropylpyridin-2-ylamino) pyridazine-3-carboxylate (150mg, 22%).¹H NMR (400MHz, chloroform-d)₆)ppm10.72(s,1H),9.23(s,1H),7.38(t,J＝8.4Hz,1H),6.79(dd,J＝8.5,2.8Hz,1H),4.57(m,2H),3.45(m,1H),1.53(m,3H),1.36(d,J＝6.9Hz,6H).

Step 6

6-chloro-4- (5-fluoro-6-isopropylpyridin-2-ylamino) pyridazine-3-carboxamide

To a solution of ethyl 6-chloro-4- (5-fluoro-6-isopropylpyridin-2-ylamino) pyridazine-3-carboxylate (290mg, 856 μmol) was added a solution of 7N ammonia in methanol (12.2mL, 85.6 mmol). The mixture was stirred at 40 ℃ for 18 h, after which time the solvent was removed to give 6-chloro-4- (5-fluoro-6-isopropylpyridin-2-ylamino) pyridazine-3-carboxamide (250mg, 94%) as an off-white solid.¹H NMR (400MHz, chloroform-d)₆)ppm11.86(s,1H),9.26(s,1H),8.19(br.s,1H),7.36(t,J＝8.8Hz,1H),6.79(dd,J＝8.5,2.8Hz,1H),5.70(br.s,1H),3.45(m,1H),1.37(d,J＝6.7Hz,6H).

Step 7

(3R,4R) -4- (6-carbamoyl-5- (5-fluoro-6-isopropylpyridin-2-ylamino) pyridazin-3-ylamino) tetra-n-ethyl Hydrogen-2H-pyrans-3-ylcarbamic acid tert-butyl ester

To a solution of 6-chloro-4- (5-fluoro-6-isopropylpyridin-2-ylamino) pyridazine-3-carboxamide (250mg, 807 μmol) in NMP (3.2mL) was added tert-butyl (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamate (174mg, 807 μmol) and the mixture was heated to 140 ℃. Over the next 36 hours, 3 more portions of tert-butyl (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamate (174mg, 807. mu. mol) were added at 12 hour intervals. At 48 h, the mixture was cooled, diluted with EtOAc, and washed with water and brine (2 ×). The organic layer was concentrated onto silica gel and purified by chromatography (70% -100% EtOAc in hexanes) to give tert-butyl (3R,4R) -4- (6-carbamoyl-5- (5-fluoro-6-isopropylpyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamate (100mg, 25%).¹H NMR (400MHz, chloroform-d)₆)ppm11.49(s,1H),8.22(s,1H),8.06(br.s,1H),7.29(t,J＝9.4Hz,1H),6.70(dd,J＝8.9,3.0Hz,1H),6.07(br.s,1H),5.50(br.s,1H),5.35(br.s,1H),4.26(br.s,1H),4.03(m,2H),3.92(d,J＝11.4Hz,1H),3.68(d,J＝11.5Hz,1H),3.61(t,J＝11.8Hz,1H),3.41(m,1H),2.24(d,J＝11.2Hz,1H),1.81(m,1H),1.49(s,9H),1.35(d,J＝6.9Hz,6H).

Step 8

6- ((3R,4R) -3-Aminotetrahydro-2H-pyran-4-ylamino) -4- (5-fluoro-6-isopropylpyridin-2-ylamino) Yl) pyridazine-3-carboxamides

To a solution of tert-butyl (3R,4R) -4- (6-carbamoyl-5- (5-fluoro-6-isopropylpyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamate (100mg, 204. mu. mol) in dichloromethane (3mL) was added trifluoroacetic acid (466mg, 315. mu.L, 4.1mmol), andthe mixture was stirred at room temperature for 16 hours. With 25% aqueous NH₄The mixture was diluted with OH, dichloromethane and water. The organic phase was separated, washed with water (2 ×), then concentrated in vacuo and purified by chromatography (silica gel, 3-10% methanol in dichloromethane) to give 6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (5-fluoro-6-isopropylpyridin-2-ylamino) pyridazine-3-carboxamide (39mg, 100 μmol, 49%) as a white solid.¹H NMR(400MHz,DMSO-d₆)ppm11.76(s,1H),8.39(s,1H),7.85(s,1H),7.65(s,1H),7.60(t,J＝9.2Hz,1H),6.88(dd,J＝8.9,2.9Hz,1H),6.78(d,J＝7.7Hz,1H),3.96(br.s,1H),3.80(m,1H),3.70(dd,J＝11.4,2.8Hz,1H),3.49(dd,J＝11.4.1.7Hz,1H),3.37(m,2H),2.96(s,1H),1.80(m,1H),1.69(m,2H),1.29(d,J＝6.8Hz,6H)；MS(EI/CI)m/z:390.2[M+H].

Example 42

6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (5-isopropyl-6-methoxypyridin-2-ylamino) pyridazine-3-carboxamide

Step 1

6-methoxy-5- (prop-1-en-2-yl) pyridin-2-amine

To a solution of 5-bromo-6-methoxypyridin-2-amine (1.72g, 8.47mmol) in dimethylacetamide (26mL) was added 4,4,5, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolan (2.07mL, 11.0mmol), tetrakis (triphenylphosphine) palladium (979mg, 847. mu. mol) and potassium phosphate (3.6g, 16.9mmol) in water (7.63mL, 424 mmol). The mixture was sealed in a microwave bottle and heated in the microwave at 150 ℃ for 15 minutes. After cooling, the reaction mixture was washed with EtOAc and Et₂The mixture was diluted O, washed with water and brine, concentrated onto silica gel and chromatographed (10% -40% EtOAc in hexane) to give 6-methoxy-5- (prop-1-en-2-yl) pyridin-2-amine, contaminated with catalyst-derivationsCrude impurity (. about.950 mg).¹HNMR (400MHz, chloroform-d)₆)ppm7.34(d,J＝8.0Hz,1H),6.06(d,J＝8.1Hz,1H),5.19(m,1H),5.09(m,1H),4.29(br.s,2H),3.91(s,3H),2.10(s,3H).

Step 2

5-isopropyl-6-methoxypyridin-2-amine

To a solution of 5-fluoro-6-isopropenyl-pyridin-2-ylamine (crude from step 1, 8.47mmol) in methanol (17.5mL) was added 10% palladium on carbon (123mg) at room temperature. A hydrogen balloon (1atm) was attached and the mixture was stirred overnight. After 18 h, the mixture was filtered through celite, concentrated onto silica gel and chromatographed (10% -40% ethyl acetate in hexanes) to give 5-isopropyl-6-methoxypyridin-2-amine (740mg, 53%, two steps).¹H NMR (400MHz, chloroform-d)₆)ppm7.26(d,J＝7.8Hz,1H),6.07(d,J＝8.1Hz,1H),4.19(br.s,2H),3.90(s,3H),3.08(m,1H),1.17(d,J＝6.9Hz,6H).

Step 3

6-chloro-4- (5-isopropyl-6-methoxypyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

To a solution of 4, 6-dichloropyridazine-3-carboxylic acid ethyl ester (1.47g, 6.64mmol) in acetonitrile (7.6mL) was added 5-isopropyl-6-methoxypyridin-2-amine (830mg, 4.99mmol) and the mixture was heated in a sealed tube at 100 ℃ for 18 h. After completion, the mixture was concentrated onto silica gel and purified by chromatography (silica gel, 10% -80% ethyl acetate in hexanes) to give ethyl 6-chloro-4- (5-isopropyl-6-methoxypyridin-2-ylamino) pyridazine-3-carboxylate (500mg, 28.5%). MS (EI/CI) M/z 351.2[ M + H ].

Step 4

6-chloro-4- (5-isopropyl-6-methoxypyridin-2-ylamino) pyridazine-3-carboxamide

To a solution of ethyl 6-chloro-4- (5-isopropyl-6-methoxypyridin-2-ylamino) pyridazine-3-carboxylate (500mg, 1.43mmol) was added a solution of 7N ammonia in methanol (20.5mL, 143 mmol). The mixture was stirred at 40 ℃ for 18 h, after which time the solvent was removed to give 6-chloro-4- (5-isopropyl-6-methoxy-pyridin-2-ylamino) -pyridazine-3-carboxamide (450mg, 98%) as an off-white solid.¹H NMR (400MHz, chloroform-d)₆)ppm11.47(s,1H),9.10(s,1H),8.17(s,1H),7.48(d,J＝8.0Hz,1H),6.53(d,J＝7.7Hz,1H),5.71(s,1H),4.04(s,3H),3.18(m,1H),1.23(d,J＝7.1Hz,6H).

Step 5

(3R,4R) -4- (6-carbamoyl-5- (5-isopropyl-6-methoxypyridin-2-ylamino) pyridazin-3-ylamino Yl) tetrahydro-2H-pyran-3-ylcarbamic acid tert-butyl ester

To a solution of 6-chloro-4- (5-isopropyl-6-methoxypyridin-2-ylamino) pyridazine-3-carboxamide (250mg, 777 μmol) in NMP (2.6mL) was added tert-butyl (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamate (672mg, 2.33mmol) in 4 portions about every 12 hours and heated to 140 ℃ during the addition. After a total of 48 hours, the mixture was cooled and then washed with ethyl acetate and brine. The phases were separated and the organic phase was then washed with brine (2 ×), concentrated in vacuo and purified by chromatography (silica gel, 0-4% 99.5:0.5 methanol: NH)₄Dichloromethane solution of OH) to give (3R,4R) -4- (6-carbamoyl-5- (5-isopropyl-6-methoxypyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro-2H-pyran-3Tert-butyl-ylcarbamate (141mg, 281. mu. mol, 36%) as a light brown solid. MS (EI/CI) M/z 502.3[ M + H ]].

Step 6

6- ((3R,4R) -3-Aminotetrahydro-2H-pyran-4-ylamino) -4- (5-isopropyl-6-methoxypyridin-2-yl) Amino) pyridazine-3-carboxamides

To a solution of tert-butyl (3R,4R) -4- (6-carbamoyl-5- (5-isopropyl-6-methoxypyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamate (141mg, 281. mu. mol) in dichloromethane (4.3mL) was added trifluoroacetic acid (641mg, 433. mu.L, 5.62mmol), and the mixture was stirred at room temperature for 16 hours. With 25% aqueous NH₄The mixture was diluted with OH, dichloromethane and water. The organic phase was separated and washed with water (2 ×), then concentrated in vacuo and purified by chromatography (silica gel, 3-10% 99.5:0.5 methanol: NH₄A solution of OH in dichloromethane) to give 6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (5-isopropyl-6-methoxypyridin-2-ylamino) pyridazine-3-carboxamide (35mg, 87 μmol, 31%) as an off-white solid.¹H NMR(400MHz,DMSO-d₆)ppm11.53(s,1H),8.37(s,1H),7.70(s,1H),7.62(s,1H),7.54(d,J＝8.1Hz,1H),6.80(d,J＝7.8Hz,1H),6.54(d,J＝8.0Hz,1H),4.05(br.s,1H),3.81(d,J＝11.9Hz,1H),3.67(dd,J＝10.9,3.5Hz,1H),3.49(dd,J＝11.1.1.9Hz,1H),3.37(m,2H),3.08(m,1H),2.97(s,1H),1.81(m,1H),1.65(m,1H),1.16(d,J＝6.8Hz,6H)；MS(EI/CI)m/z:402.3[M+H].

Example 43

6- ((3R,4R) -3-Aminotetrahydro-2H-pyran-4-ylamino) -4- (6-isopropoxypyridin-2-ylamino)

Yl) pyridazine-3-carboxamides

Step 1

6-chloro-4- (6-isopropoxypyridin-2-ylamino) pyridazine-3-carboxylic acid ethyl ester

To a solution of 4, 6-dichloropyridazine-3-carboxylic acid ethyl ester (1.63g, 7.36mmol) in acetonitrile (25mL) was added 6-isopropoxypyridin-2-amine (1.12g, 7.36mmol) and the mixture was heated at 130 ℃ for 60h in a sealed tube. After completion, the mixture was concentrated onto silica gel and purified by chromatography (20% -66% EtOAc in hexanes) to give ethyl 6-chloro-4- (6-isopropoxypyridin-2-ylamino) pyridazine-3-carboxylate (330mg, 13%). MS (EI/CI) M/z 337.1[ M + H ].

Step 2

6-chloro-4- (6-isopropoxypyridin-2-ylamino) pyridazine-3-carboxamide

To a solution of ethyl 6-chloro-4- (6-isopropoxypyridin-2-ylamino) pyridazine-3-carboxylate (530mg, 1.57mmol) was added a 7N solution of ammonia in methanol (16.9mL, 118 mmol). The mixture was stirred at 40 ℃ for 18 h, after which time the solvent was removed to give 6-chloro-4- (6-isopropoxypyridin-2-ylamino) pyridazine-3-carboxamide (470mg, 97%) as an off-white solid.¹HNMR (400MHz, chloroform-d)₆)ppm11.57(s,1H),9.08(s,1H),8.17(s,1H),7.58(t,J＝7.8Hz,1H),6.50(d,J＝7.3Hz,1H),6.44(d,J＝8.0Hz,1H),5.69(s,1H),5.23(m,1H),1.47(d,J＝6.3Hz,6H).

Step 3

(3R,4R) -4- (6-carbamoyl-5- (6-isopropoxypyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro- 2H-pyran-3-ylcarbamates

To a solution of 6-chloro-4- (6-isopropoxypyridin-2-ylamino) pyridazine-3-carboxamide (270mg, 877. mu. mol, Eq:1.00) in NMP (3.51mL) was added tert-butyl (3R,4R) -4-aminotetrahydro-2H-pyran-3-ylcarbamate (190mg, 877. mu. mol, Eq:1.00), and the mixture was heated to 140 ℃. Over the next 36 hours, an additional 3 parts of amine were added at 12 hour intervals. At 48 h, the mixture was cooled, diluted with EtOAc, and washed with water and brine (2 ×). The organic layer was concentrated onto silica gel and purified by chromatography (70% -100% EtOAc/hexanes) to give (3R,4R) -4- (6-carbamoyl-5- (6-isopropoxypyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamate (190mg, 44.4%).¹H NMR (400MHz, chloroform-d)₆)ppm11.37(s,1H),8.06(s,1H),7.92(s,1H),7.49(t,J＝7.5Hz,1H),6.44(d,J＝8.0Hz,1H),6.31(d,J＝8.2Hz,1H),5.91(s,1H),5.67(s,1H),5.38(d,J＝8.5Hz,1H),5.15(m,1H),4.30(m,1H),4.05(s,1H),4.00(d,J＝12.5Hz,1H),3.90(d,J＝12.3Hz,1H),3.68(d,J＝11.3Hz,1H),3.61(t,J＝10.8Hz,1H),2.27(s,1H),1.79(m,1H),1.44(m,15H).

Step 4

6- ((3R,4R) -3-Aminotetrahydro-2H-pyran-4-ylamino) -4- (6-isopropoxypyridin-2-ylamino) pyridazin Oxazine-3-carboxamides

To a solution of tert-butyl (3R,4R) -4- (6-carbamoyl-5- (6-isopropoxypyridin-2-ylamino) pyridazin-3-ylamino) tetrahydro-2H-pyran-3-ylcarbamate (185mg, 379. mu. mol) in dichloromethane (5.9mL) was added trifluoroacetic acid (865mg, 585. mu.L, 7.59mmol), and the mixture was stirred at room temperature for 16 hours. With 25% aqueous NH₄The mixture was diluted with OH, dichloromethane and water. The organic phase was separated and washed with water (2 ×), then concentrated in vacuo and purified by chromatographyDissolving (silica gel, 3-10% 99.5:0.5 methanol: NH)₄A solution of OH in dichloromethane) to give 6- ((3R,4R) -3-aminotetrahydro-2H-pyran-4-ylamino) -4- (6-isopropoxypyridin-2-ylamino) pyridazine-3-carboxamide (68mg, 176 μmol, 46%) as an off-white solid.¹H NMR(400MHz,DMSO-d₆)ppm11.56(s,1H),8.38(s,1H),7.62(m,3H),6.76(d,J＝7.7Hz,1H),6.54(d,J＝7.8Hz,1H),6.35(d,J＝8.2Hz,1H),5.18(m,1H),4.07(br.s,1H),3.80(d,J＝11.3Hz,1H),3.67(dd,J＝11.6,3.8Hz,1H),3.50(dd,J＝11.9.2.3Hz,1H),3.39(m,2H),2.96(s,1H),1.78(m,1H),1.68(m,2H),1.33(dd,J＝6.3,1.7Hz,6H)；MS(EI/CI)m/z:388.3[M+H].

Biological examples

SYK analysis information

Determination of IC for spleen tyrosine kinase (SYK) inhibition₅₀：

The SYK kinase assay is a standard kinase assay suitable for use in a 96 well plate format. The assay was performed in a 96 well format using 8 samples to determine IC₅₀These samples represent 10 half log dilutions and a 40 μ L reaction volume. The assay measures radiolabels³³Incorporation of P γ ATP into an N-terminal biotinylated peptide substrate derived from a naturally occurring consensus sequence of phosphorous receptors (phosphatases) (Biotin-11aa DY E). Phosphorylated products were detected after termination of the reaction with EDTA and addition of streptavidin-coated beads. Representative results are shown in table II above.

Analysis plate: 96-well MultiScreen0.65um filter plate (Millipore Cat.No.: MADVNOB10)

Streptavidin-coated beads: streptavidin Sepharose TM, suspension 5.0mL, diluted (1:100) in 50mM EDTA/PBS (Amersham, Cat. No.:17-5113-01)

A compound: 10mM in 100% Dimethylsulfoxide (DMSO), final concentration: compounds 0.003-100uM in 10% DMSO

Enzyme: recombinant human full-length SYK protein dephosphorylated by protein tyrosine phosphatase PTP1B (invitrogenccat. No.: PV4089), working solution 8.89nM, final concentration: 0.004. mu.M.

Peptide 1: biotinylated peptides were derived from the naturally occurring phosphoreceptor consensus sequence (Biotin-EPEGDYEEVLE), ordered specifically from QCB, stock 20mM, final concentration: 10 μ M.

ATP: adenosine-5' -triphosphate 20mM, (ROCHE cat. No.:93202720), final concentration: 20 μ M

Buffer solution: HEPES 2-Hydroxyethylpiperazine-2-ethanesulfonic acid (Sigma, Cat. No.: H-3375) final concentration: 50mM HEPES pH7.5

BSA: bovine serum albumin fraction V, no fatty acids (Roche Diagnostics GmbH, Cat. No.9100221), diluted to a final concentration of 0.1%

EDTA: EDTA stock solution 500mM, (GIBCO, Cat. No.:15575-038) final concentration: 0.1mM

DTT: 1, 4-dithiothreitol (Roche Diagnostics GmbH, Cat. No.:197777), final concentration: 1mM

MgCl₂x6H₂O MERCK, Cat.No. 105833.1000, final concentration: 10mM

Assay Dilution Buffer (ADB) 50mM HEPES, 0.1mM EGTA, 0.1mM sodium vanadate, 0.1mM β -glycerophosphate, 10mM MgCl₂，1mM DTT，0.1％BSA，pH7.5

Bead wash buffer: 10g/L PBS (phosphate buffered saline), containing 2M NaCl + 1% phosphoric acid.

The experimental method comprises the following steps:

18 μ L of recombinant human full-length SYK [8.89nM ] was mixed with 2 μ L of a 10X concentration solution of test compound [ typically 100 μ M-0.003 μ M ] in [ 10% ] DMSO in a 20 μ L volume and the mixture incubated for 15 minutes at room temperature.

Containing biotin peptide substrate [ 20. mu.M ] by addition of 20. mu.L of 2x]、ATP[40μM]And³³PγATP[2μCi/rxn]the substrate mixture of (a) initiates a kinase reaction. After incubation for 30 min at room temperature, by transfer25 u L reaction samples containing 100u L5mMEDTA and PBS 10% streptavidin coated beads 96 hole 0.65 m Millipore MADVNOB membrane/plate to stop the reaction.

Using 3X 250. mu.L 2M NaCl, 2X 250. mu.L 2M NaCl + 1% phosphoric acid and 1X 250. mu. L H under vacuum₂O washing the unbound radionuclide. After the last wash, the membrane/plate was transferred to the adapter plate, dried with heat at 60 ℃ for 1 hour, and 60 μ Ι _ of scintillation cocktail was added to each well, and the amount of radioactivity was counted in a top counter.

Percent inhibition was calculated based on uninhibited enzyme rate:

% inhibition ═ (1- ((test-positive control)/(negative control-positive control))) 100

IC was calculated using XLFit software (ID Business Solution Ltd., Guilford, Surrey, UK) using non-linear curve fitting₅₀。

Compound (I)	Enzyme filtration IC₅₀(μM)	Ic50 human Whole blood (. mu.M)
			I-1	0.019
I-2	0.011
			I-3	0.065
I-4	0.090
			I-5	0.098
I-6	0.464
			I-7	0.004
I-8	0.015
			I-9	0.367
I-10	0.011
			I-11	0.003
I-12	0.003
			I-13	0.020
I-14	0.003
			I-15	0.00558	0.0315
I-16	0.01697	0.15965

I-17	0.00428	0.0306
			I-18	0.0047	0.07053
I-19	0.04302	1.04462
			I-20	0.1449	31.7963
I-21	0.0051	0.4492
			I-22	0.264	21.4529
I-23	0.0089	0.8098
			I-24	0.01145	0.2365
I-25	0.00325	0.81055
			I-26	0.005	0.4327
I-27	0.0057	0.3126
			I-28	0.25245	1.5861
I-29	0.04595	1.79665
			I-30	0.0222	0.4866
I-31	0.0054	0.1964
			I-32	0.0109	0.2349
I-33		1.4157
			I-34	0.01035	0.31625
I-35	0.00205	0.92335
			I-36	0.1766	2.0892
I-37	0.24205	2.3446
			I-38	0.00175	0.6416
I-39		0.818
			I-40		0.3321
I-41		0.4944
			I-42		0.9093
I-43		0.3718

The foregoing invention has been described with some degree of particularity, by way of illustration and example, for purposes of clarity and understanding. It will be apparent to those skilled in the art that variations and modifications can be made within the scope of the claims of the present invention. Accordingly, it is to be understood that the above description is intended to be illustrative, and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but instead should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

All patents, patent applications, and publications cited in this application are hereby incorporated by reference in their entirety for all purposes as if each individual patent, patent application, or publication were individually indicated.

Claims

1. A compound of formula I

Wherein:

a is cyclohexyl or tetrahydropyranyl;

each X is independently an amino group;

m is 1;

b is phenyl, pyrrolo [2,3-B ] pyridinyl or pyrazolyl;

each Y is independentlyHalogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆Hydroxyalkyl radical, C₁-C₆Alkylsulfonyl, cycloalkyl, monocyclic aromatic heterocycle having 5 ring atoms and 3N heteroatoms, or pyrazolyl; and is

n is 0, 1 or 2;

wherein the term "cycloalkyl" refers to a saturated carbocyclic ring containing from 3 to 8 carbon atoms;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein B is pyridyl.

3. The compound of any one of claims 1-2, wherein n is 1.

4. The compound of any one of claims 1-2, wherein Y is C₁-C₆Alkyl, cycloalkyl, monocyclic aromatic heterocycle having 5 ring atoms and 3N heteroatoms, pyrazolyl or C₁-C₆An alkylsulfonyl group.

5. The compound of any one of claims 1-2, wherein Y is C₁-C₆An alkyl group.

6. The compound of any one of claims 1-2, wherein n is 2.

7. The compound of claim 6 wherein one Y is C₁-C₆Alkyl and the other is halogen or C₁-C₆An alkyl group.

8. A compound according to claim 1 wherein B is pyrrolo [2,3-B ] pyridinyl or pyrazolyl.

9. The compound of claim 1 selected from the group consisting of:

6- ((1R,2S) -2-amino-cyclohexylamino) -4-p-tolylamino-pyridazine-3-carboxamide;

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 in admixture with at least one pharmaceutically acceptable carrier, excipient or diluent.