HK1180598A

HK1180598A - Imidazopyridine and purine compounds, compositions and methods of use

Info

Publication number: HK1180598A
Application number: HK13107945.6A
Authority: HK
Inventors: Yingjie Lai; Jun Liang; Steven R. Magnuson; Vickie H. Tsui; Birong Zhang; Kirk Robarge
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 2010-03-17
Filing date: 2011-03-15
Publication date: 2013-10-25

Description

Imidazopyridine and purine compounds, compositions, and methods of use

Technical Field

The present invention relates to organic compounds useful for therapy and/or prophylaxis in a patient, in particular inhibitors of TYK2 kinase useful for the treatment of TYK2 kinase mediated diseases.

Background

Cytokine pathways mediate a wide range of biological functions, including many aspects of inflammation and immunity. Janus kinases (JAKs) include JAK1, JAK2, JAK3 and TYK2, which are cytoplasmic protein kinases associated with type I and type II cytokine receptors that regulate cytokine signal transduction. The engagement of cytokines with cognate receptors initiates the activation of receptor-associated JAKs, which leads to JAK-mediated tyrosine phosphorylation of Signaling and Transcriptional Activation (STAT) proteins, and ultimately, transcriptional activation of specific genomes. JAK1, JAK2 and TYK2 show a broad pattern of gene expression, whereas JAK3 expression is restricted to leukocytes. Cytokine receptors often function as heterodimers, and as a result, more than one type of JAK kinase is often associated with a cytokine receptor complex. The specific JAKs associated with different cytokine receptor complexes have been determined in many cases by genetic studies and confirmed by other experimental evidence.

JAK1 is functionally and physically associated with the cytokine receptor complexes of type I interferons (e.g., IFN α), type II interferons (e.g., INF γ), IL-2 and IL-6. JAK1 knockout mice die during parturition due to loss of LIF receptor signal. Characterization of tissues derived from JAK1 knockout mice demonstrates the important role of this kinase in the IFN, IL-10, IL-2/IL-4 and IL-6 pathways. The european commission recently approved a humanized monoclonal antibody targeting the IL-6 pathway (Tocilizumab) for the treatment of moderate to severe rheumatoid arthritis.

Biochemical and genetic studies have shown that JAK2 is associated with a family of single chain (e.g., EPO), IL-3, and interferon gamma cytokine receptors. Consistent with this, JAK2 knockout mice died due to anemia. Kinase activating mutations in JAK2 (e.g., JAK2V617F) are associated with human bone Marrow Proliferative Disease (MPD).

JAK3 is only associated with the gamma consensus cytokine receptor chain present in the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokine receptor complexes. JAK3 is critical for lymphocyte development and proliferation, and mutations in JAK3 result in Severe Combined Immunodeficiency (SCID). Based on their role in modulating lymphocytes, JAK3 and JAK3 mediated pathways have been targeted for immunosuppressive indications (e.g., transplant rejection and rheumatoid arthritis).

TYK2 is associated with type I interferon (e.g., IFN alpha), IL-6, IL-10, IL-12 and IL-23 cytokine receptor complexes. Consistent with this, primary cells obtained from TYK2 deficient humans are deficient in type I interferon, IL-6, IL-10, IL-12, and IL-23 signaling. The european commission recently approved fully human monoclonal antibodies (usekinumab) targeting the p40 subunit common to IL-12 and IL-23 cytokines for the treatment of moderate to severe plaque psoriasis. In addition, antibodies targeting IL-12 and IL-23 pathways have been tested clinically for the treatment of Crohn's disease.

Brief description of the invention

One embodiment includes compounds of formulae Ia-Ib:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein A, X, R¹、R²、R⁴、R⁵And R¹⁶As defined herein.

Another embodiment includes a pharmaceutical composition comprising a compound of formulae Ia-Ib, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

Another embodiment includes a method of inhibiting TYK2 kinase activity in a cell, comprising introducing into the cell a compound of formula Ia-Ib, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount effective to inhibit said kinase.

Another embodiment includes a method of treating or lessening the severity of a disease or condition responsive to inhibition of TYK2 kinase activity in a patient. The method comprises administering to the patient a therapeutically effective amount of a compound of formulae Ia-Ib, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Another embodiment includes the use of a compound of formulae Ia-Ib, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in therapy.

Another embodiment includes the use of a compound of formulae Ia-Ib, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease responsive to the inhibition of TYK2 kinase.

Another embodiment includes a process for preparing a compound of formulae Ia-Ib, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

Another embodiment includes a kit for treating a disease or disorder responsive to inhibition of TYK2 kinase. The kit includes a first pharmaceutical composition comprising a compound of formulae Ia-Ib and instructions for use.

Detailed Description

Reference will now be made in detail to some embodiments, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the claims. Those of skill in the art will recognize methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention.

Definition of

The term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon group, wherein the alkyl group may be optionally independently substituted with one or more substituents described herein. In one example, the alkyl group has 1 to 18 carbon atoms (C)₁-C₁₈). In other examples, alkyl is C₀-C₆、C₀-C₅、C₀-C₃、C₁-C₁₂、C₁-C₁₀、C₁-C₈、C₁-C₆、C₁-C₅、C₁-C₄Or C₁-C₃. Examples of alkyl groups include methyl (Me, -CH)₃) Ethyl (Et-CH)₂CH₃) 1-propyl (n-Pr, n-propyl, -CH)₂CH₂CH₃) 2-propyl (i-Pr, i-propyl, -CH (CH)₃)₂) 1-butyl (n-Bu, n-butyl, -CH)₂CH₂CH₂CH₃) 2-methyl-1-propyl (i-Bu, i-butyl, -CH)₂CH(CH₃)₂) 2-butyl (s-Bu, s-butyl, -CH (CH)₃)CH₂CH₃) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH)₃)₃) 1-pentyl (n-pentyl, -CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) 1-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂)2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂)3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃1-heptyl and 1-octyl.

The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical having at least one site of unsaturation (i.e., a carbon-carbon double bond), wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, including radicals having "cis" and "trans" orientations (or "E" and "Z" orientations). In one example, alkenyl has 2 to 18 carbon atoms (C)₂-C₁₈). In other examples, alkenyl is C₂-C₁₂、C₂-C₁₀、C₂-C₈、C₂-C₆Or C₂-C₃. Examples include, but are not limited to, ethenyl (-CH ═ CH)₂) Prop-1-enyl (-CH ═ CHCH)₃) Prop-2-enyl (-CH)₂CH＝CH₂) 2-methylpropan-1-enyl, but-2-enyl, but-3-enyl, but-1, 3-dienyl, 2-methylbut-1, 3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1, 3-dienyl.

The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical having at least one site of unsaturation (i.e., a carbon-carbon triple bond), wherein the alkynyl radical may be optionally independently substituted with one or more substituents described herein. In one example, alkynyl has 2 to 18 carbon atoms (C)₂-C₁₈). In other examples, alkynyl is C₂-C₁₂、C₂-C₁₀、C₂-C₈、C₂-C₆Or C₂-C₃. Examples include, but are not limited to, ethynyl (-C ≡ CH), prop-1-ynyl (-C ≡ CCH)₃) Prop-2-ynyl (propargyl, -CH)₂C.ident.CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.

"cycloalkyl" refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring radical, wherein the cycloalkyl radical may be optionally independently substituted with one or more substituents described herein. In one example, the cycloalkyl group has 3 to 12 carbon atoms (C)₃-C₁₂). In other examples, cycloalkyl is C₃-C₈、C₃-C₁₀Or C₅-C₁₀. In other examples, cycloalkyl as a monocyclic ring is C₃-C₄、C₃-C₆Or C₅-C₆. In another example, cycloalkyl as a bicyclic ring is C₇-C₁₂. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyl groups having 7 to 12 ring atoms include, but are not limited to, [4, 4]、[4，5]、[5，5]、[5，6]Or [6, 6 ]]A ring system. Exemplary bridged bicyclic cycloalkyl groups include, but are not limited to, bicyclo [ 2.2.1%]Heptane, bicyclo [2.2.2]Octane and bicyclo [3.2.2]Nonane.

"aryl" refers to a cyclic aromatic hydrocarbon group optionally substituted independently with one or more substituents described herein. In one example, the aryl group has 6 to 20 carbon atoms (C)₆-C₂₀). In another example, aryl is C₆-C₉. In another example, aryl is C₆And (4) an aryl group. Aryl includes bicyclic groups comprising an aromatic ring fused to a non-aromatic or partially saturated ring. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, anthracyl, indenyl, indanyl, 1, 2-dihydronaphthyl, and 1, 2-dihydronaphthyl3, 4-tetrahydronaphthyl. In one example, aryl includes phenyl. Substituted phenyl or substituted aryl means phenyl or aryl substituted by 1, 2, 3,4 or 5, e.g. 1-2, 1-3 or 1-4 substituents selected from the groups described herein. In one example, the optional substituents on the aryl group are selected from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (e.g., C)₁-C₆Alkyl), alkoxy (e.g. C)₁-C₆Alkoxy), benzyloxy, carboxyl, protected carboxyl, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulfonylaminoalkyl, heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl, or other such group. One or more of these substituents being methine (CH) and/or methylene (CH)₂) And may be substituted with similar groups as described above. Examples of the term "substituted phenyl" include mono-or di-halophenyl groups such as 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2, 6-dichlorophenyl, 2, 5-dichlorophenyl, 3, 4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3, 4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl, and the like; mono-or di- (hydroxy) phenyl such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2, 4-dihydroxyphenyl or a protected hydroxy derivative thereof, etc.; nitrophenyl, such as 3-or 4-nitrophenyl; cyanophenyl, such as 4-cyanophenyl; mono-or di- (lower alkyl) phenyl such as 4-methylphenyl, 2, 4-dimethylphenyl, 2-methylphenyl, 4- (isopropyl) phenyl, 4-ethylphenyl, 3- (n-propyl) phenyl, etc.; mono-or di- (alkoxy) phenyl such as 3, 4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-ethoxyphenyl, 4- (isopropoxy) phenyl, 4- (tert-butoxy) phenyl, 3-ethoxy-4-methoxyphenyl, etc.; 3-or 4-trifluoromethylphenyl; mono-or di-carboxyphenyl or (protected carboxy) phenyl such as 4-carboxyphenyl, mono-or di- (hydroxymethyl) phenyl or (protected hydroxymethyl) phenyl such as 3- (protected hydroxymethyl) phenyl or 3, 4-di (hydroxymethyl) phenylYlmethyl) phenyl; mono-or di- (aminomethyl) phenyl or (protected aminomethyl) phenyl such as 2- (aminomethyl) phenyl or 2, 4- (protected aminomethyl) phenyl; or mono-or di- (N- (methylsulfonylamino)) phenyl such as 3- (N-methylsulfonylamino)) phenyl. Likewise, the term "substituted phenyl" also denotes disubstituted phenyl groups wherein the substituents are different, such as 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl and the like; trisubstituted phenyl groups wherein the substituents are different, such as 3-methoxy-4-benzyloxy-6-methylsulfonylamino, 3-methoxy-4-benzyloxy-6-phenylsulfonylamino; and tetrasubstituted phenyl groups wherein the substituents are different, such as 3-methoxy-4-benzyloxy-5-methyl-6-phenylsulfonylamino. Specific substituted phenyl groups include 2-chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl, 3, 4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4- (1-chloromethyl) benzyloxy-6-methylsulfonylaminophenyl. The fused aryl ring may also be substituted with any, e.g., 1, 2, or 3, of the substituents described herein in a manner similar to substituted alkyl.

"halo" or "halogen" refers to F, Cl, Br or I.

The terms "heterocycle" and "heterocyclyl" are used interchangeably herein to mean: (i) a saturated or partially unsaturated cyclic group (i.e., having one or more double and/or triple bonds in the ring) ("heterocycloalkyl") or (ii) an aromatic cyclic group ("heteroaryl"), in each case at least one ring atom being a heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur, the remaining ring atoms being carbon. The heterocyclyl group may be optionally substituted with one or more substituents described below. In one embodiment, heterocyclyl includes those having 1-9 carbon ring members (C)₁-C₉) And the remaining ring atoms are a heteroatom selected from N, O, S and P. In other examples, heterocyclyl includes those having C₁-C₅、C₃-C₅Or C₄-C₅And the remaining ring atoms are monocyclic or bicyclic rings selected from N, O, S and P. In some embodiments, heterocyclyl includes a 3-10, 3-7, or 3-6 membered ring containing one or more heteroatoms independently selected from N, O, S and P. In other examples, heterocyclyl includes 3-, 4-, 5-, 6-, or 7-membered rings containing one or more heteroatoms independently selected from N, O, S and P. In another embodiment, heterocyclyl includes bi-or polycyclic, spiro, or bridged 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered ring systems containing one or more heteroatoms independently selected from N, O, S and P. Examples of bicyclic ring systems include, but are not limited to [3, 5 ]]、[4，5]、[5，5]、[3，6]、[4，6]、[5，6]Or [6, 6 ]]Provided is a system. Examples of bridged ring systems include, but are not limited to, [2.2.1 ] having 1 to 3 heteroatoms selected from N, O, S and P]、[2.2.2]、[3.2.2]And [4.1.0]And (4) arranging. In another embodiment, heterocyclyl includes spirocyclic groups having 1 to 4 heteroatoms selected from N, O, S and P. The heterocyclyl group may be a carbon-attached group or a heteroatom-attached group. "Heterocyclyl" includes heterocyclyl groups fused to cycloalkyl groups.

Exemplary heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1, 2-dithiocyclobutyl, 1, 3-dithiocyclobutyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thianaphthenyl, and the likeAlkyl, piperazinyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepinyl, oxazepinylRadicals, oxazepinyl, diazepanyl, 1, 4-diazepanyl, diazepineThio-aza radicalA group, thiazepin, dihydrothienyl, dihydropyranyl, dihydrofuryl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanylAlkyl, 1, 3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0]Hexyl, 3, 6-diazabicyclo [3.1.1]Heptyl, 6-azabicyclo [3.1.1]Heptyl, 3-azabicyclo [3.1.1]Heptyl, 3-azabicyclo [4.1.0]Heptyl, 2-oxa-6-azaspiro [3.3]]Heptyl and azabicyclo [2.2.2]And hexyl. Examples of heterocyclyl groups in which the ring atom is substituted by oxo (═ O) are pyrimidinone groups and 1, 1-dioxo-thiomorpholinyl groups. The heterocyclyl groups herein are optionally substituted independently with one or more substituents described herein. Heterocycles are described in the following documents: pattette, leoa.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), particularly chapters 1, 3,4, 6,7 and 9; "The Chemistry of heterocyclic Compounds, A series of monograms" (John Wiley&Sons, new york, 1950 to date), particularly volumes 13, 14, 16, 19 and 28; and j.am.chem.soc. (1960) 82: 5566.

the term "heteroaryl" refers to an aromatic carbocyclic group in which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen and sulfur, and the remaining ring atoms are carbon. Heteroaryl groups may be optionally substituted with one or more substituents described herein. In one example, the heteroaryl group contains 1-9 carbon ring atoms (C)₁-C₉). In other examples, heteroaryl is C₁-C₅、C₃-C₅Or C₄-C₅. In one embodiment, exemplary heteroaryl groups include 5-10 or 5-6 membered rings or monocyclic aromatic 5-, 6-, and 7-membered rings containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. In a further embodiment of the process according to the invention,exemplary heteroaryl groups include fused ring systems having up to 10, or in another example up to 9, carbon atoms, wherein at least one aromatic ring contains one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. "heteroaryl" includes heteroaryl groups fused to aryl, cycloalkyl or other heterocyclic groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, imidazopyridyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoiylAzolyl, thiazolyl,Oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, cinnolinyl,Oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolylAzolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl and furopyridinyl.

In some embodiments, heterocyclyl or heteroaryl is C-linked. By way of non-limiting example, a carbon-bonded heterocyclyl includes the bonding arrangement at the following positions: position 2, 3,4, 5 or 6 for pyridine, position 3,4, 5 or 6 for pyridazine, position 2, 4, 5 or 6 for pyrimidine, position 2, 3,5 or 6 for pyrazine, position 2, 3,5 or 6 for furan, tetrahydrofuran, thiolene, thiophene, pyrrole or tetrahydropyrrole,2, 4 or 5 positions of azoles, imidazoles or thiazolesPosition 3,4 or 5 of oxazole, pyrazole or isothiazole, position 2 or 3 of aziridine, position 2, 3 or 4 of azetidine, position 2, 3,4, 5,6, 7 or 8 of quinoline, or position 1, 3,4, 5,6, 7 or 8 of isoquinoline. (2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl).

In some embodiments, heterocyclyl or heteroaryl is N-linked. By way of non-limiting example, a nitrogen-bonded heterocyclyl or heteroaryl group includes the bonding arrangement at the following positions: aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, position 1 of 1H-indazole, position 2 of isoindoline or isoindoline, position 4 of morpholine, position 9 of carbazole or β -carboline.

"treatment" refers to both therapeutic treatment and prophylactic or preventative measures, the object of which is to prevent or slow down (lessen) an undesired physiological change or disorder, such as cancer development or spread. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (i.e., not worsening) of the disease state, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment (partially or completely) (detectable or undetectable), or diminishment of persistence and inhibition of relapse. "treatment" may also refer to an extended survival compared to the expected survival without treatment. Those in need of treatment include those already with the condition or disorder as well as those predisposed to the condition or disorder (e.g., by genetic mutation) or in which prevention of the condition or disorder is anticipated.

The phrase "therapeutically effective amount" means an amount of a compound of the invention that (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow to some extent, preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent, preferably stop) tumor metastasis; inhibit tumor growth to some extent; and/or relieve to some extent one or more symptoms associated with cancer. A drug may be cytostatic and/or cytotoxic if it can achieve a degree of preventing growth and/or killing of existing cancer cells. For cancer treatment, efficacy can be measured, for example, by assessing time to disease progression (TTP) and/or determining Response Rate (RR). In the case of an immune disease, a therapeutically effective amount is an amount sufficient to reduce or alleviate symptoms of an allergic disorder, autoimmune and/or inflammatory disease, or symptoms of an acute inflammatory response (e.g., asthma). In some embodiments, a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly reduce B cell activity or number.

As used herein, "inflammatory disease" may refer to any disease, disorder or condition in which an excessive or uncontrolled inflammatory response results in excessive inflammatory symptoms, host tissue damage or loss of tissue function. "inflammatory disease" also refers to a pathological condition mediated by leukocyte influx and/or neutrophil chemotaxis.

As used herein, "inflammation" refers to a local protective response caused by tissue damage or destruction that serves to destroy, dilute, or separate (isolate) harmful substances from damaged tissue. Inflammation is significantly accompanied by leukocyte influx and/or neutrophil chemotaxis. Inflammation can result from infection by pathogenic organisms and viruses and from non-infectious means such as trauma or reperfusion following myocardial infarction or stroke, immune responses to foreign antigens, and autoimmune responses. Thus, inflammatory diseases that may be treated with compounds of formulae Ia-Ib include disorders related to the response of specific defense systems as well as the response of non-specific defense systems.

By "specific defense system" is meant that components of the immune system respond to the presence of a particular antigen. Examples of inflammation resulting from reactions of the specific defense system include classical responses to foreign antigens, autoimmune diseases and delayed type hypersensitivity responses (mediated by T-cells). Chronic inflammatory diseases, rejection of transplanted solid tissues and organs such as kidney and bone marrow transplantation, and Graft Versus Host Disease (GVHD) are other examples of inflammatory responses of specific defense systems.

The term "non-specific defense system" as used herein refers to inflammatory diseases mediated by leukocytes (such as granulocytes and macrophages) capable of generating an immunological memory. Examples of inflammation arising, at least in part, from reactions of the non-specific defense system include inflammation associated with conditions such as: adult (acute) respiratory distress syndrome (ARDS) or multiple organ impairment syndrome; reperfusion injury; acute glomerulonephritis; reactive arthritis; skin diseases associated with acute inflammatory components; acute purulent meningitis or other central nervous system inflammatory diseases such as stroke; heat damage; inflammatory bowel disease; -granulocyte transfusion-related syndrome; and cytokine-induced toxicity.

As used herein, "autoimmune disease" refers to any collection of diseases in which tissue damage is associated with a humoral or cell-mediated response to a body's own components.

As used herein, "allergic disease" refers to any symptom resulting from an allergy, tissue damage, or loss of tissue function. As used herein, "arthritic disease" refers to any disease characterized by inflammatory injury to the joints attributable to various etiologies. As used herein, "dermatitis" refers to any of a large family of skin diseases characterized by skin inflammation attributable to various etiologies. As used herein, "transplant rejection" refers to any immune response against a transplanted tissue, such as an organ or cell (e.g., bone marrow), characterized by loss of function of the transplanted or surrounding tissue, pain, swelling, leukocytosis, and thrombocytopenia. The therapeutic methods of the present invention include methods for treating disorders associated with inflammatory cell activation.

"inflammatory cell activation" refers to the induction of a proliferative cellular response by stimuli (including but not limited to cytokines, antigens or autoantibodies), the production of soluble mediators (including but not limited to cytokines, oxygen radicals, enzymes, prostanoids or vasoactive amines) or the cell surface expression of new or increased numbers of mediators (including but not limited to major histocompatibility antigens or cell adhesion molecules) in inflammatory cells (including but not limited to monocytes, macrophages, T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclear leukocytes such as neutrophils, basophils and eosinophils), mast cells, dendritic cells, langerhans cells and endothelial cells). It will be appreciated by those skilled in the art that activation of one or a combination of these phenotypes in these cells can lead to the initiation, perpetuation or exacerbation of an inflammatory disease.

The term "NSAID" is short for "nonsteroidal anti-inflammatory drug" which is a therapeutic agent with analgesic, antipyretic (reduced elevated body temperature for pain relief without compromising perception) and anti-inflammatory effects at higher doses (reduced inflammation). The term "non-steroidal" is used to distinguish these drugs from steroids, which (among a wide range of other effects) have similar eicosanoid inhibitory, anti-inflammatory effects. NSAIDs are unusual as analgesics because they are non-hypnotic. NSAIDs include aspirin, ibuprofen, and naproxen. NSAIDs are generally indicated for the treatment of acute or chronic conditions in which pain and inflammation are present. NSAIDs are generally indicated for symptomatic relief of the following conditions: rheumatoid arthritis, osteoarthritis, inflammatory joint diseases (e.g., ankylosing spondylitis, psoriatic arthritis, reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, post-operative pain, mild to moderate pain due to inflammation and tissue injury, fever, ileus, and renal colic. most NSAIDs act as non-selective inhibitors of cyclooxygenase, inhibiting both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes cyclooxygenase catalyzes the synthesis of arachidonic acid (which itself is catalyzed by phospholipase A)₂Derived from a cellular phospholipid bilayer) to form prostaglandinsAnd thromboxane. Prostaglandins act (among other things) as messenger molecules in the inflammatory process. COX-2 inhibitors include celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, and valdecoxib.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in a patient that is often characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma (carcinoma), lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer (including small-cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung, and squamous carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer.

A "chemotherapeutic agent" is a substance that can be used to treat a given condition, such as cancer or an inflammatory condition. Examples of chemotherapeutic agents include NSAIDs; hormones, such as glucocorticoids; corticosteroids such as hydrocortisone, hydrocortisone acetate, cortisone acetate, ticortol pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, triamcinolone (triamcinolone alcohol), mometasone, amcinolone acetonide, budesonide, desonide, fluocinolone acetonide, halcinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone dipropionate, prednisone, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednide acetate; immunoselective anti-inflammatory peptides (ImSAID), e.g. phenylalanine-glutamine-glycine (FEG) andits D-isomer form (feG) (IMULAN BioTherapeutics, LLC); antirheumatic agents, for example azathioprine, cyclosporine (cyclosporin A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, Methotrexate (MTX), minocycline, sulfasalazine, cyclophosphamide, tumor necrosis factor alpha (TNF alpha) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), cetolizumab (Cimzia), golimumab (Simponi), interleukin 1(IL-1) blockers such as anakinra (Kineret), anti-B cell monoclonal antibodies such as rituximabT cell co-stimulation blockers such as abercapt (oracia), interleukin 6(IL-6) blockers such as tocilizumab; hormone antagonists, such as tamoxifen, finasteride or LHRH antagonists; radioisotope (e.g. At)²¹¹、I¹³¹、I¹²⁵、Y⁹⁰、Re¹⁸⁶、Re¹⁸⁸、Sm¹⁵³、Bi²¹²、P³²、Pb²¹²And radioactive isotopes of Lu); miscellaneous test agents (miscellaneoustingpesticide), such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH₃Or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavin, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors, such as chloroquine; alkylating agents, such as thiotepa and cyclophosphamideAlkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimines and methylmelamines including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylmelamine; acetogenins (especially bullatacin and bullatacin)); delta-9-tetrahydroCannabinol (dronabinol,) (ii) a Beta-lapachone (lapachone); lapachol; colchicine; betulinic acid; camptothecin (including the synthetic analogue topotecan)CPT-11 (irinotecan,) Acetyl camptothecin, scopolectin and 9-aminocamptothecin); bryostatins; callystatin; CC-1065 (including its aldorexin, kazelaixin, and bizelaixin synthetic analogs); podophyllotoxin; podophyllinic acid; (ii) teniposide; nostoc cyclopeptides (in particular nostoc cyclopeptide 1 and nostoc cyclopeptide 8); dolastatin; doxocarmycin (duocarmycin) (including the synthetic analogs KW-2189 and CB1-TM 1); (ii) an elutherobin; pancratistatin; sarcodictyin; spongistatin (spongistatin); nitrogen mustards, such as chlorambucil, chlorophosphamide, estramustine, ifosfamide, mechlorethamine (mechlorethamine), mechlorethamine hydrochloride, melphalan, neomustard, benzene mustard cholesterol, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorouramicin, fotemustine, lomustine, nimustine and ranimustine; antibiotics, such as enediynes (enediyne) antibiotics (e.g., calicheamicins, particularly calicheamicin γ 1I and calicheamicin ω I1 (see, e.g., Nicolaou et al, Angew. chem Intl. Ed. Engl., 33: 183-) -186 (1994)); CDP323, an oral α -4 integrin inhibitor, dynemicin, including dynemicin A; esperamicin, and neocarcinomycin chromophore and related tryptophane diyne antibiotic chromophores), aclacinomycin (aclacinomysin), actinomycin, anthranomycin (authramycin), azaserine, bleomycin, actinomycin, carminomycin, carzinomycin, tryptomycin, actinomycin D, daunorubicin, ditallo-5-oxo-L-norleucine, doxoracine (including C, carabicin)Morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolidino-doxorubicin, doxorubicin hydrochloride liposome injectionLiposomal doxorubicin TLC D-99Pegylated liposomal doxorubicinAnd doxorubicine), epirubicin, esorubicin, idarubicin, masaromycin, mitomycins such as mitomycin C, mycophenolic acid, norramycin, olivomycin, pellomycin, pofiomycin, puromycin, triiron doxorubicin (quelemycin), rodoribicin (rodorubicin), streptonigrin (streptonigrin), streptozocin, tubercidin (ubenimex), stastatin (zinostatin), zorubicin; antimetabolites, e.g. methotrexate, gemcitabineTegafurCapecitabineEpothilone and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine (dideoxyuridine), doxifluridine, enocitabine, floxuridine; androgens such as carroterone, drostandrosterone propionate, epitioandrostanol, meperidine, testolactone; anti-adrenal-glands, e.g. aminoglutethimide,Mitotane, trilostane; folic acid supplements, such as folinic acid (frilic acid); acetic acid glucurolactone; (ii) an aldophosphamide glycoside; aminolevulinic acid; eniluracil (eniluracil); amsacrine; bestrabuucil; a bisantrene group; edatrexate (edatraxate); defofamine; colchicine; diazaquinone (diaziqutone); elfornitine; ammonium etiolate; an epothilone; etoglut; gallium nitrate; a hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine (maytansine) and ansamitocins (ansamitocins); mitoguazone (mitoguzone); mitoxantrone; mopidamol (mopidamol); nitraminoacrridine (nitracrine); pentostatin; methionine mustard (phenamett); pirarubicin; losoxanthraquinone; 2-ethyl hydrazide; procarbazine;polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane (rizoxane); rhizomycin; sizofuran (sizofiran); a germanium spiroamine; tenuizonic acid (tenuazonic acid); triimine quinone (triaziquone); 2,2 ', 2' -trichlorotriethylamine; trichothecenes (trichothecenes), especially T-2 toxin, veracurin A, bacillocin A (roridin A) and serpentin (anguidine)); uratan; vindesineDacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobromane (pipobroman); a polycytidysine; arabinoside ("Ara-C"); thiotepa; taxanes (taxoids), e.g. paclitaxelAlbumin engineered nanoparticle formulation (ABRAXANE) of paclitaxel^TM) And docetaxelChlorambucil (chlorenbucil); 6-thioguanine; mercaptopurine; methotrexate; platinum agents, e.g. cisplatin, oxaliplatin (e.g. as) And carboplatin; vinca alkaloids (vincas) for preventing tubulin polymerization to form microtubules, including vinblastineVincristineVindesineAnd vinorelbineEtoposide (VP-16); ifosfamide; mitoxantrone; leucovorin (leucovorin); norfloxacin (novantrone); edatrexae; daunomycin; aminopterin; ibandronic acid or salts or esters thereof; topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); retinoids, e.g. fenretinide, retinoic acid, including bexaroteneBisphosphonic acid drugs, e.g. clodronic acid or salts or esters thereof (e.g. clodronic acid)OrEtidronic acid or a salt or ester thereofNE-58095, zoledronic acid/zoledronic acid salts or estersAlendronic acid or salts or esters thereofPamidronic acid or a salt or ester thereofTelufonic acid or salt or ester thereofOr risedronic acid or salts or esters thereofTroxacitabine (1, 3-dioxolane nucleoside cytosine analogue); antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways involved in abnormal cell proliferation, such as PKC- α, Ralf, H-Ras and epidermal growth factor receptor (EGF-R); vaccines, e.g.Vaccines and gene therapy vaccines, e.g.A vaccine,A vaccine anda vaccine; topoisomerase 1 inhibitors (e.g. topoisomerase 1 inhibitors)) (ii) a rmRH (e.g. rmRH)) (ii) a BAY439006 (Sorafenib; Bayer); SU-11248 (sunitinib,pfizer); perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteasome inhibitors (e.g., PS 341); bortezomibCCI-779; tipifarnib (R11577); orafenaib, ABT 510; bcl-2 inhibitors, e.g. oblimersen sodiumAnthraquinone; EGFR inhibitors (see definition below); farnesyl transferase inhibitors, e.g. lonafarnib (SCH 6636, SARASAR)^TM) (ii) a And a pharmaceutically acceptable salt, acid or derivative of any of the above; and combinations of two or more of the foregoing, e.g., CHOP (abbreviation for cyclophosphamide, doxorubicin, vincristine, and prednisolone combination therapy) and FOLFOX (oxaliplatin)^TM) Abbreviation for treatment regimen combining 5-FU and folinic acid).

Other chemotherapeutic agents as defined herein also include "anti-hormonal agents" or "endocrine therapeutic agents" which modulate, reduce, block or inhibit the effects of hormones capable of promoting cancer growth. They may be hormones themselves, including but not limited to: antiestrogens with mixed agonist/antagonist properties, including tamoxifen4-hydroxy tamoxifen, toremifeneIdoxifene, droloxifene, raloxifeneTravoxifene, keoxifene, and Selective Estrogen Receptor Modulators (SERMs), such as SERM 3; pure antiestrogens without agonist properties, e.g. fulvestrantAnd EM800 (such agents can block Estrogen Receptor (ER) dimerization, inhibit DNA binding, increase ER turnover, and/or suppress ER levels); aromatase inhibitors, including steroidal aromatase inhibitors such as formestane and exemestaneAnd non-steroidal aromatase inhibitors such as anastrozoleLetrozoleAnd aminoglutethimide and other aromatase inhibitors including vorozoleMegestrol acetateFadrozole and 4(5) -imidazoles; luteinizing hormone releasing hormone agonists including leuprolide (A)And) Goserelin, buserelin and triptorelin; sex steroids including pregnanes (progestines) such as megestrol acetate and medroxyprogesterone acetate, estrogens, such as diethylstilbestrol and prometharine, and androgens/retinoids, such as fluoxymesterone, all-trans retinoic acid and fenretinide; onapristone (onapristone); antiprogestins; estrogen receptor down-regulator (ERD); antiandrogenic drugs such as flutamide, nilutamide and bicalutamide.

Additional chemotherapeutic agents include therapeutic antibodies, such as alemtuzumab (Campath), bevacizumab (bGenentech); cetuximab (Imclone); panitumumab (A)Amgen), rituximab (Genentech/Biogen Idec), pertuzumab (2C4, Genentech), trastuzumab (Genentech)、lebrikizumab、tocilizumab(Roche), tositumomab (Bexxar, Corixia) and antibody drug conjugate gemumab ozomicin (r) ((r)Wyeth). Other humanized monoclonal antibodies that have therapeutic potential as active agents in combination with the compounds of the invention include: aprezumab (apilizumab), aselizumab (aselizumab), atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, celelizumab (cedelizumab), certolizumab pegol, cidfusituzumab, ciduzumab, daclizumab, eculizumab (eculizumab), efuzumab (efalizumab), epruzumab (eprizumab), nonvzuzumab (feluzumab), aryltuzumab (fontollizumab), gimuzumab, influzumab (inolizumab), inolizumab (inolizumab), ipilizumab (lapuzumab), lindolizumab (lindolizumab), poluzumab (lindolizumab), influzumab (influzumab), influzumab (inolizumab), inolizumab (linuzumab), influzumab (linuzumab), ipiuzumab (linumab), philizumab (reluzumab), influzumab (zeuzumab), influzumab (reluzumab), influzumab (zeuzumab), influzumab (linumab), influzumab (reluzumab), influzumab (influzumab), influzumab (influzumab)izumab, rayleigh monoclonal antibody (resizumab), resyvizumab, rovizumab (rovelizumab), lulizumab (ruplizumab), sibutrumab (sibutrumab), sibutrumab (siprozumab), solizuzumab (solvizumab), natuzumab (situzumab), tacatuzumab tetraxetan, tadocizumab (talizumab), tefibuzumab (tefibuzumab), tosituzumab (tocilizmab), tolizumab (tolizumab), tolizumab (toralizumab), tuzumab celluliukin, tucusituzumab, umab, umazumab, ubuzumab (uretuzumab), and anti-interleukin-12 (ABT-874/J, resyee) with full-length recombinant human immunoglobulin sequences of recombinant human IgG 8584, which is recognized as interleukin-12 by human antibody series 8512.

Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise interact directly with EGFR and inhibit or reduce its signaling activity, which are otherwise also referred to as "EGFR antagonists. Examples of such agents include antibodies and small molecules that bind EGFR. Examples of EGFR-binding antibodies include MAb 579(ATCC CRL HB 8506), MAb 455(ATCC CRL HB8507), MAb 225(ATCC CRL 8508), MAb 528(ATCCCRL 8509) (see Mendelsohn et al, US patent 4,943,533) and variants thereof such as chimeric 225(C225 or cetuximab;) And modified human 225(H225) (see WO96/40210, Imclone Systems Inc.); IMC-11F8, which is a fully human EGFR-targeting antibody (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in U.S. patent No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or panitumumab (see WO98/50433 to Abgenix/Amgen); EMD 55900 (Straglioto et al, Eur. J. cancer 32A: 636-640 (1996)); EMD7200(matuzumab), a humanized EGFR antibody directed against EGFR and competing with EGF and TGF- α for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (genmab); fully human antibodies designated E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and described in US 6,235,883; MDX-447(Medarex Inc.); and mAb806 or humanized mAb806 (Johns et al, J.biol.chem.279 (29): 30375-30384 (2004)). anti-EGFR antibodies can be conjugated to cytotoxic agents, thereby generating an immunoconjugate (see, e.g., EP 659,439a2, Merck Patent GmbH). EGFR antagonists include small molecules such as those described in U.S. patents 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, and PCT publications WO98/14451, WO98/50038, WO99/09016, and WO 99/24037. Specific small molecule EGFR antagonists include OSI-774(CP-358774, erlotinib,Genentech/OSI Pharmaceuticals); PD 183805(CI 1033, 2-propenamide, N- [4- [ (3-chloro-4-fluorophenyl) amino)]-7- [3- (4-morpholinyl) propoxy]-6-quinazolinyl]Dihydrochloride, Pfizer Inc.); ZD 1839, gefitinib (iressa j)4- (3 '-chloro-4' -fluoroanilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline, AstraZeneca); ZM 105180 ((6-amino-4- (3-methylphenyl-amino) -quinazoline, Zeneca); BIBX-1382(N8- (3-chloro-4-fluoro-phenyl) -N2- (1-methyl-piperidin-4-yl) -pyrimido [5, 4-d)]Pyrimidine-2, 8-diamine, boehringer ingelheim); PKI-166((R) -4- [4- [ (1-phenylethyl) amino)]-1H-pyrrolo [2, 3-d]Pyrimidin-6-yl]-phenol); (R) -6- (4-hydroxyphenyl) -4- [ (1-phenylethyl) amino group]-7H-pyrrolo [2, 3-d]Pyrimidines); CL-387785(N- [4- [ (3-bromophenyl) amino)]-6-quinazolinyl]-2-butynylamide); EKB-569(N- [4- [ (3-chloro-4-fluorophenyl) amino group]-3-cyano-7-ethoxy-6-quinolinyl]-4- (dimethylamino) -2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571(SU 5271; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors, e.g. lapatinib (C.)GSK572016 or N- [ 3-chloro-4- [ (3-fluorophenyl) methoxy]Phenyl radical]-6[5[ [ [ 2-methylsulfonyl group ]]Ethyl radical]Amino group]Methyl radical]-2-furyl radical]-4-quinazolinesAn amine.

Chemotherapeutic agents also include "tyrosine kinase inhibitors" which include the EGFR-targeting drugs mentioned in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda; CP-724, 714, which is an oral ErbB2 receptor tyrosine kinase selective inhibitor (Pfizer and OSI); dual HER inhibitors that preferentially bind EGFR but inhibit HER2 and EGFR-overexpressing cells such as EKB-569 (available from Wyeth); lapatinib (GSK 572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors, such as canatinib (CI-1033; Pharmacia); raf-1 inhibitors, such as antisense agents available from ISIS Pharmaceuticals, ISIS-5132, which inhibit Raf-1 signaling; non-HER targeted TK inhibitors, such as imatinib mesylate (GLEEVECJ, available from Glaxo SmithKline); multiple targeted tyrosine kinase inhibitors such as sunitinib (b)Available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); CI-1040, an inhibitor of MAPK extracellular regulated kinase I (available from Pharmacia); quinazoline drugs such as PD 153035, 4- (3-chloroanilino) quinazoline; a pyridopyrimidine drug; a pyrimidopyrimidine drug; pyrrolopyrimidine drugs such as CGP 59326, CGP 60261, and CGP 62706; pyrazolopyrimidine drug, 4- (phenylamino) -7H-pyrrolo [2, 3-d]A pyrimidine drug; curcumin (diferuloylmethane, 4, 5-bis (4-fluoroanilino) -phthalimide); tyrphostins containing nitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acids); quinoxaline drugs (us patent 5,804,396); trypostins (U.S. patent 5,804,396); ZD6474(Astra Zeneca); PTK-787(Novartis/Schering AG); pan-HER inhibitors, such as CI-1033 (Pfizer); affinitac (ISIS 3521; ISIS/Lilly); imatinib mesylate (GLEEVECJ); PKI 166 (Novartis); GW2016(Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); semaxinib (pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/ScheringAG); INC-1C11 (Imclone); rapamycin (a compound of formula I) is rapamycin (sirolimus,) (ii) a Or as described in any of the following patent publications: us patent 5,804,396; WO 1999/09016(American Cyanamid); WO 1998/43960(American Cyanamid); WO1997/38983(Warner Lambert); WO 1999/06378(Warner Lambert); WO1999/06396(Warner Lambert); WO 1996/30347(Pfizer, Inc); WO1996/33978 (Zeneca); WO1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

Unless otherwise indicated, "optionally substituted" means that the group may be unsubstituted or substituted with one or more (e.g., 0, 1, 2, 3, or 4) of the substituents listed for the group, wherein the substituents may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents. In another embodiment, the optionally substituted group has 3 substituents.

The term "prodrug" as used in this application refers to a precursor or derivative form of a pharmaceutically active substance that is less effective in patients or cytotoxic to tumor cells than the parent drug and is capable of being activated or converted to the more effective parent form by enzyme or hydrolysis. See, e.g., Wilman, "Prodrugs in Cancer chemistry," Biochemical Society Transactions, 14, pp.375-382, 615, Belfast (1986) and Stella et al, "Prodrugs: AChesical Approach to Targeted Drug Delivery, "Directed Drug Delivery, Borchardt et al, (ed.) pp.247-. Prodrugs of the present invention include, but are not limited to, phosphate group-containing prodrugs, thiophosphate group-containing prodrugs, sulfate group-containing prodrugs, peptide-containing prodrugs, D-amino acid modified prodrugs, glycosylated prodrugs, β -lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosine and other 5-fluorouridine prodrugs, which can be converted to the more active cytotoxic free drug. Examples of cytotoxic drugs that may be derivatized into prodrug forms for use in the present invention include, but are not limited to, those chemotherapeutic agents described above.

The term "package insert" is used to refer to instructions typically included in commercial packaging for a therapeutic product that contain information regarding the indications, uses, dosages, administrations, contraindications and/or warnings associated with the use of the therapeutic product.

The term "stereoisomers" refers to compounds having the same chemical composition but differing in the arrangement of atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers, and the like.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography.

"enantiomer" refers to two stereoisomers of a compound that are mirror images of each other that are not superimposable.

The stereochemical definitions and conventions used herein generally follow the general definitions of S.P. Parker, eds, McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to its chiral center (S). The prefixes d and l or (+) and (-) are used to designate the sign of a compound that rotates plane polarized light, where (-) or l denotes that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is commonly referred to as a mixture of enantiomers. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, which are not optically active.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted through a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.

The phrase "pharmaceutically acceptable salt" as used herein refers to pharmaceutically acceptable organic or inorganic salts of the compounds of formulae Ia-Ib. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, iso-hydrochloride, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate)). Pharmaceutically acceptable salts may involve the inclusion of other molecules, such as acetate, succinate, or other counterions. The counter ion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. Moreover, a pharmaceutically acceptable salt may have more than one charged atom in its structure. The case where the multiply charged atom is part of a pharmaceutically acceptable salt may have multiple counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterions.

"solvate" refers to an association or complex of one or more solvent molecules with a compound of formula Ia-Ib. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

The term "leaving group" or "Lv" refers to a group or moiety of a first reactant in a chemical reaction from which it leaves in the chemical reaction. Examples of leaving groups include, but are not limited to, halogen atoms, alkoxy groups, and sulfonyloxy groups. Examples of sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups such as methylsulfonyloxy (mesylate) and trifluoromethylsulfonyloxy (triflate) and arylsulfonyloxy groups such as p-toluenesulfonyloxy (tosylate) and p-nitrobenzenesulfonyloxy (nitrobenzenesulfonate).

The term "protecting group" or "Pg" refers to a substituent that is commonly used to block or protect a particular functional group while reacting other functional groups on a compound. For example, an "amino protecting group" is a substituent attached to an amino group in a compound that blocks or protects the amino functionality. Suitable amino protecting groups include acetyl, trifluoroacetyl, phthalimido, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" is a substituent of a hydroxyl that blocks or protects the hydroxyl functionality. Suitable hydroxy protecting groups include acetyl, trialkylsilyl, dialkylphenylsilyl, benzoyl, benzyl, benzyloxymethyl, methyl, methoxymethyl, triarylmethyl, and tetrahydropyranyl. "carboxy protecting group" refers to a substituent of a carboxy group that blocks or protects the carboxy functionality. Common carboxyl protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfinyl)Yl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl, and the like. For a general description of the protecting groups and their use, see T.W.Greene and P.Wuts, protective groups in Organic Synthesis, third edition, John Wiley&Sons, new york, 1999; and p.kocienski, Protecting Groups, third edition, Verlag, 2003.

The term "patient" includes both human patients and animal patients. The term "animal" includes companion animals (e.g., dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species.

The phrase "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith.

Unless otherwise indicated, the term "compounds of the present invention" includes compounds of formulae Ia-Ib and stereoisomers, tautomers, solvates, prodrugs and salts (e.g., pharmaceutically acceptable salts) thereof. Unless otherwise indicated, structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, wherein one or more hydrogen atoms are replaced by deuterium or tritium or one or more carbon atoms are enriched¹³C-or¹⁴Carbon-substituted compounds of formulae Ia and Ib of C-are included within the scope of the invention.

TYK2 inhibitor compounds

In one embodiment, compounds of formulae Ia-Ib, or stereoisomers or pharmaceutically acceptable salts thereof, and pharmaceutical formulations are provided that are useful for the treatment of diseases, conditions and/or disorders that respond to the inhibition of TYK 2.

Another embodiment includes compounds of formulae Ia-Ib or stereoisomers or pharmaceutically acceptable salts thereof,

wherein:

a is CR³Or N;

x is CR¹⁵Or N;

R¹independently of one another is hydrogen, halogen, C₁-C₃Alkyl radical, C₃-C₄Cycloalkyl, -CF₃、-OR⁶、-SR⁶、-OCF₃、-CN、-NO₂、-NR⁶SO₂R⁷、-NR⁶C(O)R⁷or-NR⁶R⁷Wherein two R are¹Not both hydrogen, and wherein said alkyl and cycloalkyl groups are optionally substituted by halogen, OR⁶、-NR⁶R⁷Or phenyl substitution;

R²and R³Independently of each other is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, - (C)₀-C₃Alkyl) CN, - (C)₀-C₃Alkyl) OR⁸、-(C₀-C₃Alkyl) SR⁸、-(C₀-C₃Alkyl) NR⁸R⁹、-(C₀-C₃Alkyl) CF₃、-O(C₀-C₃Alkyl) CF₃、-(C₀-C₃Alkyl) NO₂、-(C₀-C₃Alkyl group C (O) R⁸、-(C₀-C₃Alkyl) C (O) OR⁸、-(C₀-C₃Alkyl group C (O) NR⁸R⁹、-(C₀-C₃Alkyl) NR⁸C(O)R⁹、-(C₀-C₃Alkyl) S (O)_1-2R⁸、-(C₀-C₃Alkyl) NR⁸S(O)_1-2R⁹、-(C₀-C₃Alkyl) S (O)_1-2NR⁸R⁹、-(C₀-C₃Alkyl) (C₃-C₆Cycloalkyl), - (C)₀-C₃Alkyl) (3-6 membered heterocyclyl), - (C)₀-C₃Alkyl) (5-6 membered heteroaryl) or- (C)₀-C₃Alkyl) phenyl, wherein R²And R³Independently is optionally substituted by R¹⁰Substitution;

R⁴is-NH₂、-NH-、-NR⁶R⁷、-NR⁶C(O)-、-NR⁶C(O)O-、-NR⁶C(O)NR⁷-、-NR⁶S(O)_1-2-or-NR⁶S(O)_1-2NR⁷-；

R⁵Absent or hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₈Cycloalkyl, phenyl or 3-10 membered heterocyclyl, wherein R⁵Optionally substituted with R¹⁰Substitution;

R⁶and R⁷Each independently is hydrogen, C₁-C₃Alkyl or C₃-C₄Cycloalkyl, wherein said alkyl and cycloalkyl are independently optionally substituted by halogen, oxo, -OR¹¹or-NR¹¹R¹²Substitution; or

R⁶And R⁷Independently form, together with the atom to which they are attached, an optionally substituted halogen, oxo, -NR¹¹R¹²Or C₁-C₃An alkyl-substituted 3-6 membered heterocyclyl;

R⁸and R⁹Each independently is hydrogen, C₁-C₃Alkyl radical, C₃-C₆Cycloalkyl, phenyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein said alkyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl is independently optionally substituted with R¹⁰Substitution; or

R⁸And R⁹Independently form, together with the atom to which they are attached, an optionally substituted halogen, oxo, -NR¹¹R¹²Or C₁-C₃An alkyl-substituted 3-6 membered heterocyclyl;

R¹⁰independently is hydrogen, oxo, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, - (C)₀-C₃Alkyl) CN, - (C)₀-C₃Alkyl) OR¹¹、-(C₀-C₃Alkyl) SR¹¹、-(C₀-C₃Alkyl) NR¹¹R¹²、-(C₀-C₃Alkyl) CF₃、-(C₀-C₃Alkyl) NO₂、-C＝NH(OR¹¹)、-(C₀-C₃Alkyl group C (O) R¹¹、-(C₀-C₃Alkyl) C (O) OR¹¹、-(C₀-C₃Alkyl group OC (O) R¹¹、-(C₀-C₃Alkyl) OC (O) OR¹¹、-(C₀-C₃Alkyl group C (O) NR¹¹R¹²、-(C₀-C₃Alkyl) NR¹¹C(O)R¹²、-(C₀-C₃Alkyl) NR¹¹C(O)OR¹²、-(C₀-C₃Alkyl group OC (O) NR¹¹R¹²、-(C₀-C₃Alkyl) S (O)_1-2R¹¹、-(C₀-C₃Alkyl) NR¹¹S(O)_1-2R¹²、-(C₀-C₃Alkyl) S (O)_1-2NR¹¹R¹²、-(C₀-C₃Alkyl) (C₃-C₈Cycloalkyl), - (C)₀-C₃Alkyl) (3-10 membered heterocyclyl), - (C)₀-C₃Alkyl) C (O) (3-10 membered heterocyclyl) or- (C₀-C₃Alkyl) phenyl, wherein R¹⁰Independently optionally substituted with: halogen, oxo, -CF₃、-(C₀-C₃Alkyl) OR¹³、-(C₀-C₃Alkyl) NR¹³R¹⁴、-(C₀-C₃Alkyl group C (O) R¹³、-(C₀-C₃Alkyl) S (O)_1-2R¹³3-to 10-membered heterocyclic group or C₁-C₃Alkyl, optionally substituted by oxo, halogen, -NR¹³R¹⁴OR-OR¹³And (4) substitution.

R¹¹And R¹²Independently of each other is hydrogen, C₁-C₆Alkyl or- (C)₀-C₃Alkyl) phenyl, wherein the alkyl and phenyl are independently optionally substituted by halogen, oxo, -OR¹³、-NR¹³R¹⁴、C₁-C₃Alkyl, - (C)₀-C₃Alkyl) (C₃-C₆Cycloalkyl), - (C)₀-C₃Alkyl) phenyl, - (C)₀-C₃Alkyl) (3-6 membered heterocyclyl) or- (C₀-C₃Alkyl) (5-6 membered heteroaryl) substituted; or

R¹¹And R¹²Together with the atom to which they are attached form an optionally halogen-, oxo-OR¹³、-NR¹³R¹⁴Or C₁-C₃An alkyl-substituted 3-6 membered heterocyclyl;

R¹³and R¹⁴Independently of each other is hydrogen, C₁-C₆Alkyl, OH or O (C)₁-C₆Alkyl), wherein the alkyl is optionally substituted by halogen, -NH₂、-N(CH₃)₂Or oxo; or

R¹³And R¹⁴Together with the atom to which they are attached form an optionally halogen-, oxo-or-NH group₂、-N(CH₃)₂Or C₁-C₃An alkyl-substituted 3-6 membered heterocyclyl;

R¹⁵is hydrogen, halogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, - (C)₀-C₃Alkyl) CN, - (C)₀-C₃Alkyl) OR¹⁸、-(C₀-C₃Alkyl) SR¹⁸、-(C₀-C₃Alkyl) NR¹⁸R¹⁹、-(C₀-C₃Alkyl) CF₃、-O(C₀-C₃Alkyl) CF₃、-(C₀-C₃Alkyl) NO₂、-(C₀-C₃Alkyl group C (O) R¹⁸、-(C₀-C₃Alkyl) C (O) OR¹⁸、-(C₀-C₃Alkyl group C (O) NR¹⁸R¹⁹、-(C₀-C₃Alkyl) NR¹⁸C(O)R¹⁹、-(C₀-C₃Alkyl) S (O)_1-2R¹⁸、-(C₀-C₃Alkyl) NR¹⁸S(O)_1-2R¹⁹、-(C₀-C₃Alkyl) S (O)_1-2NR¹⁸R¹⁹、-(C₀-C₃Alkyl) (C₃-C₆Cycloalkyl), - (C)₀-C₃Alkyl) (3-6 membered heterocyclyl), - (C)₀-C₃Alkyl) (5-6 membered heteroaryl) or- (C)₀-C₃Alkyl) phenyl, wherein R¹⁵Optionally substituted with R¹⁰Substitution;

R¹⁶is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, - (C)₀-C₃Alkyl) CN, - (C)₁-C₃Alkyl) OR¹⁸、-(C₁-C₃Alkyl) SR¹⁸、-(C₁-C₃Alkyl) NR¹⁸R¹⁹、-(C₁-C₃Alkyl) CF₃、-O(C₁-C₃Alkyl) CF₃、-(C₂-C₃Alkyl) NO₂、-(C₀-C₃Alkyl group C (O) R¹⁸、-(C₀-C₃Alkyl) C (O) OR¹⁸、-(C₀-C₃Alkyl) C (═ NR)¹⁸)NR¹⁸R¹⁹、-(C₀-C₃Alkyl group C (O) NR¹⁸R¹⁹、-(C₀-C₃Alkyl) NR¹⁸C(O)R¹⁹、-(C₀-C₃Alkyl) S (O)_1-2R¹⁸、-(C₀-C₃Alkyl) NR¹⁸S(O)_1-2R¹⁹、-(C₀-C₃Alkyl) S (O)_1-2NR¹⁸R¹⁹、-(C₀-C₃Alkyl) (C₃-C₆Cycloalkyl), - (C)₀-C₃Alkyl) (3-6 membered heterocyclyl), - (C)₀-C₃Alkyl) (5-6 membered heteroaryl) or- (C)₀-C₃Alkyl) phenyl, wherein R¹⁶Optionally substituted with R¹⁰Substitution;

R¹⁸and R¹⁹Independently hydrogen OR optionally substituted by halogen, oxo, CN, -OR²⁰、-SR²⁰or-NR²⁰R²¹Substituted C₁-C₆An alkyl group; or

R¹⁸And R¹⁹Together with the atoms to which they are attached form optionally substituted halogen, oxo, C₁-C₃Alkyl, CN, -OR²⁰、-SR²⁰or-NR²⁰R²¹A substituted 3-6 membered heterocyclyl; and is

R²⁰And R²¹Independently hydrogen or optionally oxo, -OH or-NH₂Substituted C₁-C₆An alkyl group.

Some embodiments include compounds of formulae Ia-Ib, or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

a is CR³Or N;

x is CR¹⁵Or N;

R⁵Absent or hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, phenyl, 3-7 membered heterocyclyl or 5-10 membered heteroaryl, wherein R⁵Optionally substituted with R¹⁰Substitution;

R⁶And R⁷Independently of the source to which they are attachedTogether forming an optionally substituted halogen, oxo, -NR¹¹R¹²Or C₁-C₃An alkyl-substituted 3-6 membered heterocyclyl;

R¹⁰independently is hydrogen, oxo, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, - (C)₀-C₃Alkyl) CN, - (C)₀-C₃Alkyl) OR¹¹、-(C₀-C₃Alkyl) SR¹¹、-(C₀-C₃Alkyl) NR¹¹R¹²、-(C₀-C₃Alkyl) CF₃、-(C₀-C₃Alkyl) NO₂、-C＝NH(OR¹¹)、-(C₀-C₃Alkyl group C (O) R¹¹、-(C₀-C₃Alkyl) C (O) OR¹¹、-(C₀-C₃Alkyl group C (O) NR¹¹R¹²、-(C₀-C₃Alkyl) NR¹¹C(O)R¹²、-(C₀-C₃Alkyl) S (O)_1-2R¹¹、-(C₀-C₃Alkyl) NR¹¹S(O)_1-2R¹²、-(C₀-C₃Alkyl) S (O)_1-2NR¹¹R¹²、-(C₀-C₃Alkyl) (C₃-C₆Cycloalkyl), - (C)₀-C₃Alkyl) (3-6 membered heterocyclyl), - (C)₀-C₃Alkyl group of C (O) (3-6 membered heterocyclic group), - (C)₀-C₃Alkyl) (5-6 membered heteroarylBase) or- (C)₀-C₃Alkyl) phenyl, wherein R¹⁰Independently optionally substituted by halogen, C₁-C₃Alkyl, oxo, -CF₃、-(C₀-C₃Alkyl) OR¹³、-(C₀-C₃Alkyl) NR¹³R¹⁴、-(C₀-C₃Alkyl group C (O) R¹³Or- (C)₀-C₃Alkyl) S (O)_1-2R¹³Substitution;

R¹⁶is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, - (C)₀-C₃Alkyl) CN, - (C)₁-C₃Alkyl) OR¹⁸、-(C₁-C₃Alkyl) SR¹⁸、-(C₁-C₃Alkyl) NR¹⁸R¹⁹、-(C₁-C₃Alkyl) CF₃、-O(C₁-C₃Alkyl) CF₃、-(C₂-C₃Alkyl) NO₂、-(C₀-C₃Alkyl group C (O) R¹⁸、-(C₀-C₃Alkyl) C (O) OR¹⁸、-(C₀-C₃Alkyl group C (O) NR¹⁸R¹⁹、-(C₀-C₃Alkyl) NR¹⁸C(O)R¹⁹、-(C₀-C₃Alkyl) S (O)_1-2R¹⁸、-(C₀-C₃Alkyl) NR¹⁸S(O)_1-2R¹⁹、-(C₀-C₃Alkyl) S (O)_1-2NR¹⁸R¹⁹、-(C₀-C₃Alkyl) (C₃-C₆Cycloalkyl), - (C)₀-C₃Alkyl) (3-6 membered heterocyclyl), - (C)₀-C₃Alkyl) (5-6 membered heteroaryl) or- (C)₀-C₃Alkyl) phenyl, wherein R¹⁶Optionally substituted with R¹⁰Substitution;

R¹⁸and R¹⁹Independently hydrogen or optionally substituted by halogen, oxo, CN or-NR²⁰R²¹Substituted C₁-C₆An alkyl group; or

R¹⁸And R¹⁹Together with the atoms to which they are attached form optionally substituted halogen, oxo, C₁-C₃Alkyl, CN or-NR²⁰R²¹A substituted 3-6 membered heterocyclyl; and is

R²⁰And R²¹Independently is hydrogen or C₁-C₆An alkyl group.

In some embodiments, formulas Ia-Ib include compounds other than:

2- (6-amino-7H-purin-8-yl) phenol;

2- (2-fluoro-3-methoxyphenyl) -N- (pyridin-4-ylmethyl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

8- (2, 4-dichlorophenyl) -7H-purin-6-amine;

2- (2, 5-dimethoxyphenyl) -N-methyl-3H-imidazo [4, 5-c ] pyridin-4-amine;

8- (2, 3,5, 6-tetrafluoro-4- (1H-imidazol-1-yl) phenyl) -7H-purin-6-amine; and

8-o-tolyl-7H-purin-6-amine.

In some embodiments, a is CR³。

In some embodiments, a is CR³And X is CR¹⁵。

In some embodiments, a is CR³And X is N.

In some embodiments, a is N.

In some embodiments, A is N and X is CR¹⁵。

In some embodiments, a is N and X is N.

In some embodiments, R¹Independently of one another is hydrogen, halogen, C₁-C₃Alkyl, -CF₃、-OR⁶、-SR⁶、-OCF₃、-NO₂or-NR⁶R⁷Wherein two R are¹Not both hydrogen, and wherein the alkyl group is optionally substituted by halogen, OR⁶or-NR⁶R⁷And (4) substitution.

In some embodiments, R¹Independently hydrogen, F, Cl, Br, -OH, -CF₃、-OCF₃、-CH₃or-OCH₃Wherein two R are¹Not both hydrogen.

In some embodiments, R¹Independently a halogen. In one embodiment, R¹Independently F or Cl. In another embodiment, R¹Is Cl.

In some embodiments, R¹Independently of one another is halogen, R⁴is-NHR⁵、-NR⁶C(O)R⁵、-NR⁶C(O)OR⁵or-NR⁶C(O)NR⁷R⁵Wherein R is⁵Is not hydrogen.

In some embodiments, one R is¹Is halogen and R⁴is-NHR⁵or-NR⁶C(O)R⁵Wherein R is⁵Is not hydrogen.

In some embodiments, one R is¹Is halogen and the other R¹Is hydrogen, halogen, C₁-C₃Alkyl radical, C₃-C₄Cycloalkyl, -CF₃、-OH、-O(C₁-C₃Alkyl), -SH, -S (C)₁-C₃Alkyl), -OCF₃、-CN、-NO₂、-NHSO₂CH₃、-NHC(O)R⁷or-NR⁶R⁷Wherein said alkyl and cycloalkyl groups are optionally substituted by halogen, OR⁸、-NR⁸R⁹Or phenyl substitution.

In some embodiments, one R is¹Is halogen and the other R¹Is halogen, C₁-C₃Alkyl radical, C₃-C₄Cycloalkyl, -CF₃、-OH、-O(C₁-C₃Alkyl), -SH, -S (C)₁-C₃Alkyl), -OCF₃、-CN、-NO₂、-NHSO₂CH₃、-NHC(O)R⁷or-NR⁶R⁷Wherein said alkyl and cycloalkyl groups are optionally substituted by halogen, OR⁸、-NR⁸R⁹Or phenyl substitution.

In some embodiments, R¹Independently of one another is halogen, C₁-C₃Alkyl radical, C₃-C₄Cycloalkyl, -CF₃、-OH、-O(C₁-C₃Alkyl), -SH, -S (C)₁-C₃Alkyl), -OCF₃、-CN、-NO₂、-NHSO₂CH₃、-NHC(O)R⁷or-NR⁶R⁷Wherein said alkyl and cycloalkyl groups are optionally substituted by halogen, OR⁸、-NR⁸R⁹Or phenyl substitution.

In some embodiments, R¹Independently of each other hydrogen, F, Cl, -CF₃、-CH₃or-OCF₃Wherein two R are¹Not both hydrogen.

In some embodiments, R²Independently is hydrogen, halogen or optionally substituted by R¹⁰Substituted C₁-C₆An alkyl group. In some embodimentsIn, R²Independently F, Cl, Br, -CH₂OH、-CH₂NH₂or-CH₂A morpholino group.

In some embodiments, R²Independently hydrogen or halogen.

In some embodiments, R²Is hydrogen.

In some embodiments, R³Is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, - (C)₀-C₃Alkyl) CN, - (C)₀-C₃Alkyl) OR⁸、-(C₀-C₃Alkyl) SR⁸、-(C₀-C₃Alkyl) NR⁸R⁹、-(C₀-C₃Alkyl group C (O) NR⁸R⁹、-(C₀-C₃Alkyl) S (O)_1-2R⁸Or- (C)₀-C₃Alkyl) (3-6 membered heterocyclyl), wherein R³Independently is optionally substituted by R¹⁰And (4) substitution.

In some embodiments, R³Is hydrogen, Cl, F, Br, -CH₃Ethynyl, -NH₂、-CN、-S(O)₂CH₃、-C(O)NH₂、-CH₂NH₂、-CH₂OH、-CH₂NH(CH₃)、-CH₂N(CH₃)₂or-CH₂A morpholino group in a group of amino acids,

in some embodiments, R³Is hydrogen, halogen, -CN or-S (O)_1-2(C₁-C₃Alkyl groups). In one embodiment, R³Is hydrogen, -CN or-S (O)₂CH₃。

In some embodiments, a is CR³，R²Is hydrogen, and R³Is hydrogen, halogen, -CN or-S (O)_1-2(C₁-C₃Alkyl groups).

In some embodiments, having a structureIs selected from the group consisting of:

wherein the wavy line represents the point of attachment in formula I.

In some embodiments, R⁴is-NH-, -NR⁶C(O)-、-NR⁶C (O) O-or-NR⁶C(O)NR⁷-。

In some embodiments, R⁴is-NHR⁵、-NR⁶C(O)R⁵、-NR⁶C(O)OR⁵or-NR⁶C(O)NR⁷R⁵。

In some embodiments, R⁴is-NHR⁵、-NR⁶C(O)R⁵、-NR⁶C(O)OR⁵or-NR⁶C(O)NR⁷R⁵Wherein R is⁵Is not hydrogen.

In some embodiments, X is CR¹⁵And R is⁴is-NHR⁵、-NR⁶C(O)R⁵、-NR⁶C(O)OR⁵or-NR⁶C(O)NR⁷R⁵。

In some embodiments, R⁴is-NR⁶C(O)R⁵、-NR⁶C(O)OR⁵or-NR⁶C(O)NR⁷R⁵。

In some embodiments, R⁴is-NH₂And R is⁵Is absent.

In some embodiments, R⁴is-NHR⁵or-NR⁶C(O)R⁵Wherein R is⁵Is not hydrogen.

In some embodiments, R⁵Is absent.

In some embodiments, R⁵Is hydrogen.

In some embodiments, R⁴is-NR⁶R⁷、-NR⁶C(O)NR⁷-or-NR⁶S(O)_1-2NR⁷-；R⁵Is absent; and R is⁶And R⁷Independently of each other is hydrogen, C₁-C₃Alkyl or C₃-C₄Cycloalkyl, wherein said alkyl and cycloalkyl are independently optionally substituted by halogen, oxo, -OR¹¹or-NR¹¹R¹²And (4) substitution.

In some embodiments, R⁵Is optionally substituted by R¹⁰Substituted C₁-C₆An alkyl group. In some embodiments, R⁵Is methyl, ethyl, isopropyl, tert-butyl, -CH₂OH、-CH₂N(CH₃)₂or-CH₂NHC(O)OC(CH₃)₃。

In some embodiments, R⁵Is C optionally substituted by halogen₁-C₆An alkyl group. In some embodiments, R⁵Is methyl, ethyl, isopropyl or tert-butyl.

In some embodiments, R⁵Is optionally substituted by R¹⁰Substituted C₃-C₆A cycloalkyl group.

In some embodiments, R⁵Is cyclopropyl, cyclobutyl,Wherein the wavy lines represent the points of attachment in formulae Ia to Ib.

In some embodiments, R⁵Is a taskC optionally substituted by halogen₃-C₆A cycloalkyl group. In some embodiments, R⁵Is cyclopropyl optionally substituted by halogen. In some embodiments, R⁵Selected from:

wherein the wavy lines represent the points of attachment in formulae Ia to Ib.

In some embodiments, R⁵Is optionally substituted by R¹⁰A substituted phenyl group. In some embodiments, R⁵Is phenyl. In some embodiments, R⁵Is optionally substituted by-O (CH)₂)₂Pyrrolidinyl-substituted phenyl.

In some embodiments, R⁵Is optionally substituted by R¹⁰Substituted 3-10 membered heterocyclyl. In some embodiments, R⁵Is optionally substituted by R¹⁰Substituted pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, triazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, pyrrolidinyl, pyrimidinonyl, pyrimidinylyl, and their pharmaceutically acceptable salts,Azolyl radical, isoOxazolyl, isothiazolyl, or thiazolyl.

In some embodiments, R⁵Is optionally substituted by R¹⁰Substituted 3-7 membered heterocyclyl.

In some embodiments, R⁵Is optionally substituted by R¹⁰Substituted 5-10 membered heteroaryl. In some embodiments, R⁵Is optionally substituted by R¹⁰Substituted pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, triazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl,Azolyl radical, isoOxazolyl, isothiazolyl, or thiazolyl. In some embodiments, R⁵Is pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, pyrazinyl, pyridazinyl,Azolyl or isoxazolylAzolyl, wherein said R⁵Optionally substituted with R¹⁰And (4) substitution. In some embodiments, R⁵Is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, triazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl,Azolyl radical, isoAzolyl, isothiazolyl or thiazolyl, optionally substituted by C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, halogen, -CN, -OR¹¹、-SR¹¹、-CF₃、-NR¹¹R¹²、-NR¹¹C(O)R¹²、-C＝NH(OR¹¹)、-C(O)OR¹¹、-C(O)NR¹¹R¹²、-C(O)R¹¹-C (O)3-6 membered heterocyclyl or 3-6 membered heterocyclyl, wherein the alkyl is optionally substituted by oxo, halogen, -NR¹³R¹⁴、-OR¹³Or 3-10 membered heterocyclyl, and said heterocyclyl is optionally substituted with: oxo, halogen, -NR¹³R¹⁴、-OR¹³3-6 membered heterocyclyl or C₁-C₃Alkyl, optionally substituted by halogen OR OR¹¹And (4) substitution.

In some embodiments, R⁵Is pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, pyrazinylA pyridazinyl group,Azolyl or isoxazolylAzolyl radical, optionally substituted by C₁-C₆Alkyl, halogen, -CN, -O (C)₀-C₃Alkyl), -CF₃、-NR¹¹R¹²、-C＝NH(OR¹¹)、-C(O)OR¹¹3-6 membered heterocyclyl, wherein said alkyl is optionally substituted with halogen OR OR¹¹And said heterocyclyl is optionally substituted with: oxo, halogen or C₁-C₃Alkyl, optionally substituted by halogen OR OR¹¹And (4) substitution.

In some embodiments, R⁵Is a 5-6 membered heteroaryl group, wherein R⁵Optionally substituted with R¹⁰Is substituted in which R¹⁰Is C₁-C₆Alkyl, halogen, -CN, -OR¹¹、-SR¹¹、-NR¹¹R¹²、-CF₃、-C(O)R¹¹、-C(O)OR¹¹、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹²、-S(O)_1-2R¹¹、-NR¹¹S(O)_1-2R¹²、-S(O)_1-2NR¹¹R¹²、C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, -C (O) (3-6 membered heterocyclyl), 5-6 membered heteroaryl or phenyl, wherein R¹⁰Independently optionally substituted by halogen, C₁-C₃Alkyl, oxo, -CF₃、-OR¹³、-NR¹³R¹⁴、-C(O)R¹³or-S (O)_1-2R¹³And (4) substitution. In one example, R⁵Is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thienyl, pyrazolyl, pyranyl, triazolyl, iso-pyridylAzolyl group,Oxazolyl, imidazolyl, thiazolyl or thiadiazolyl, wherein R⁵Optionally substituted by 1, 2 or 3R¹⁰And (4) substitution.

In some embodiments, R⁵Is a pyridyl group, optionally substituted with: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, - (C)₀-C₃Alkyl) CN, - (C)₀-C₃Alkyl) OR¹¹、-(C₀-C₃Alkyl) SR¹¹、-(C₀-C₃Alkyl) NR¹¹R¹²、-(C₀-C₃Alkyl) CF₃、-(C₀-C₃Alkyl) NO₂、-C＝NH(OR¹¹)、-(C₀-C₃Alkyl group C (O) R¹¹、-(C₀-C₃Alkyl) C (O) OR¹¹、-(C₀-C₃Alkyl group C (O) NR¹¹R¹²、-(C₀-C₃Alkyl) NR¹¹C(O)R¹²、-(C₀-C₃Alkyl) S (O)_1-2R¹¹、-(C₀-C₃Alkyl) NR¹¹S(O)_1-2R¹²、-(C₀-C₃Alkyl) S (O)_1-2NR¹¹R¹²、-(C₀-C₃Alkyl) (C₃-C₆Cycloalkyl), - (C)₀-C₃Alkyl) (3-6 membered heterocyclyl), - (C)₀-C₃Alkyl group of C (O) (3-6 membered heterocyclic group), - (C)₀-C₃Alkyl) (5-6 membered heteroaryl) or- (C)₀-C₃Alkyl) phenyl, wherein R¹⁰Independently optionally substituted by halogen, C₁-C₃Alkyl, oxo, -CF₃、-(C₀-C₃Alkyl) OR¹³、-(C₀-C₃Alkyl) NR¹³R¹⁴、-(C₀-C₃Alkyl group C (O) R¹³Or- (C)₀-C₃Alkyl) S (O)_1-2R¹³And (4) substitution.

In some embodiments, R⁵Selected from:

wherein the wavy lines represent the points of attachment in formulae Ia to Ib.

In some embodiments, R⁵Is pyrimidinyl, pyridazinyl, triazinyl or pyrazinyl, optionally substituted by R¹⁰And (4) substitution.

In some embodiments, R⁵Is pyrimidinyl, pyridazinyl or pyrazinyl, optionally substituted with: c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, - (C)₀-C₃Alkyl) CN, - (C)₀-C₃Alkyl) OR¹¹、-(C₀-C₃Alkyl) SR¹¹、-(C₀-C₃Alkyl) NR¹¹R¹²、-(C₀-C₃Alkyl) CF₃、-(C₀-C₃Alkyl) NO₂、-C＝NH(OR¹¹)、-(C₀-C₃Alkyl group C (O) R¹¹、-(C₀-C₃Alkyl) C (O) OR¹¹、-(C₀-C₃Alkyl group C (O) NR¹¹R¹²、-(C₀-C₃Alkyl) NR¹¹C(O)R¹²、-(C₀-C₃Alkyl) S (O)_1-2R¹¹、-(C₀-C₃Alkyl) NR¹¹S(O)_1-2R¹²、-(C₀-C₃Alkyl) S (O)_1-2NR¹¹R¹²、-(C₀-C₃Alkyl) (C₃-C₆Cycloalkyl), - (C)₀-C₃Alkyl) (3-6 membered heterocyclyl), - (C)₀-C₃Alkyl group of C (O) (3-6 membered heterocyclic group), - (C)₀-C₃Alkyl) (5-6 membered heteroaryl) or- (C)₀-C₃Alkyl) phenyl, wherein R¹⁰Independently optionally substituted by halogen, C₁-C₃Alkyl, oxo, -CF₃、-(C₀-C₃Alkyl) OR¹³、-(C₀-C₃Alkyl) NR¹³R¹⁴、-(C₀-C₃Alkyl group C (O) R¹³Or- (C)₀-C₃Alkyl) S (O)_1-2R¹³And (4) substitution.

In some embodiments, R⁵Selected from:

wherein the wavy lines represent the points of attachment in formulae Ia to Ib. In some embodiments, R⁵Is pyrazolyl, isoAzolyl group,Oxazolyl, imidazolyl, thiazolyl, isothiazolyl or thiadiazolyl, wherein R⁵Optionally substituted with R¹⁰And (4) substitution. In some embodiments, R⁵Is pyrazolyl, isoAzolyl group,Azolyl, imidazoleA group, thiazolyl or thiadiazolyl, wherein R⁵Optionally substituted with R¹⁰Is substituted in which R¹⁰Is C₁-C₆Alkyl, halogen, -CN, -OR¹¹、-SR¹¹、-NR¹¹R¹²、-CF₃、-C(O)R¹¹、-C(O)OR¹¹、-C(O)NR¹¹R¹²、-NR¹¹C(O)R¹²、-S(O)_1-2R¹¹、-NR¹¹S(O)_1-2R¹²、-S(O)_1-2NR¹¹R¹²、C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, -C (O) (3-6 membered heterocyclyl), 5-6 membered heteroaryl or phenyl, wherein R¹⁰Independently optionally substituted by halogen, C₁-C₃Alkyl, oxo, -CF₃、-OR¹³、-NR¹³R¹⁴、-C(O)R¹³or-S (O)_1-2R¹³And (4) substitution.

In some embodiments, R⁵Selected from:

wherein the wavy lines represent the points of attachment in formulae Ia to Ib.

In some embodiments, R⁵Is a pyrrolopyrimidinyl, pyrazolopyrimidinyl group, wherein R⁵Optionally substituted with R¹⁰And (4) substitution. In some embodiments, R⁵Selected from:wherein the wavy lines represent the points of attachment in formulae Ia to Ib.

In some embodiments, R⁵Is a pyrimidinone group, optionally substituted by R¹⁰And (4) substitution. In some embodiments, R⁵Is that

In some embodiments, R⁵Is hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CH₂OH、-CH₂N(CH₃)₂、-CH₂NHC(O)OC(CH₃)₃Cyclopropyl, cyclobutyl,Phenyl, phenyl,

In some embodiments, R¹⁰Is selected from C₁-C₆Alkyl radical, C₁-C₆Alkenyl radical, C₁-C₆Alkynyl, C₃-C₆Cycloalkyl, halogen, -CN, -OR¹¹、-CH₂OR¹¹、-SR¹¹、-CF₃、-NR¹¹R¹²、-NR¹¹C(O)R¹²、-C＝NH(OR¹¹)、-C(O)R¹¹、-C(O)OR¹¹、-NR¹¹C(O)OR¹²、-C(O)NR¹¹R¹²-C (O)3-10 membered heterocyclyl or 3-10 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl are independently optionally oxo, -halogen, -NR¹³R¹⁴、-OR¹³Or 3-to 10-membered heterocyclic ringAnd said cycloalkyl and heterocyclyl are independently optionally substituted with: oxo, halogen, -NR¹³R¹⁴、-OR¹³、-C(O)R¹³3-to 10-membered heterocyclic group or C₁-C₃Alkyl, optionally substituted by halogen, -NR¹³R¹⁴OR OR¹³And (4) substitution.

In some embodiments, R¹⁰Is C₁-C₆Alkyl, halogen, -CN, -OR¹¹、-SR¹¹、-NR¹¹R¹²、-CF₃、-C＝NH(OR¹¹)、-C(O)OR¹¹、C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, wherein R¹⁰Independently optionally substituted by halogen, C₁-C₃Alkyl, oxo, -CF₃、-OR¹³、-NR¹³R¹⁴、-C(O)R¹³or-S (O)_1-2R¹³And (4) substitution.

In some embodiments, R¹⁰Is oxo, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH₂OH、F、Cl、-N(CH₃)₂、-CN、-C＝NH(OCH₃)、-OH、-OCH₃、-NH₂、-NHCH₃、-N(CH₃)₂、-CH₂NH₂、-CH₂NHCH₃、-CH₂N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂-C (O) morpholinyl, -CH₂Morpholinyl, 1-hydroxyethyl, 4-oxetanylpiperazinyl, 2-oxa-6-azaspiro [3.3]Heptyl, -C (O) H, -CO₂H、-COCH₃、-SCH₃1-carboxycycloprop-1-yl, -C (O) pyrrolidinyl, 4-fluoroazacyclobutyl, -NHC (O) CH₃、-NHC(O)CH₂CH₃-C (O) azetidinyl, -C (O) (4-hydroxyazetidinyl), -C (O) NH (1, 1-dimethyl-2-hydroxyethyl), -CO₂CH₃、-CF₃Morpholinyl, pyrrolidinyl, azetidinyl, 4-hydroxyazetidinyl, 1-dioxothiomorpholinyl, N-methylpiperazinylN- (2-hydroxyethyl) piperazinyl, 4- (2-hydroxyethyl) piperazinyl, 2-hydroxypropyl, 4-hydroxypiperidinyl, 1, 2-dihydroxyethyl, 3-hydroxypyrrolidinyl, 2, 5-dihydroxymethylpyrrolidinyl, 2, 5-dihydroxyethylpyrrolidinyl, -NHC (O) Ot-butyl, -NH (CH)₂)₂OH、-NCH₃(CH₂)₂OH or-O (CH)₂)₂A pyrrolidinyl group.

In some embodiments, R¹⁰Is methyl, -CH₂OH、F、Cl、-N(CH₃)₂、-CN、-C＝NH(OCH₃)、-OCH₃、-CO₂CH₃、-CF₃Morpholinyl, pyrrolidinyl, azetidinyl, 1-dioxothiomorpholinyl, N-methylpiperazinyl, N- (2-hydroxyethyl) piperazinyl, 4-hydroxypiperidinyl, 2, 5-dihydroxymethylpyrrolidinyl, 2, 5-dihydroxyethylpyrrolidinyl, -NH (CH)₂)₂OH、-NCH₃(CH₂)₂OH or-O (CH)₂)₂A pyrrolidinyl group.

In some embodiments, R¹⁰Selected from:

wherein the wavy lines represent the points of attachment in formulae Ia to Ib.

In some embodiments, R¹¹And R¹²Independently hydrogen OR optionally substituted by halogen, oxo, -OR¹³、-NR¹³R¹⁴、C₃-C₆Cycloalkyl, phenyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl substituted C₁-C₆Alkyl, OR together with the atoms to which they are attached form an optionally halogen-, oxo-OR¹³、-NR¹³R¹⁴Or C₁-C₃Alkyl-substituted 3-6 membered heterocyclyl.

In some embodiments, R¹¹And R¹²Independently hydrogen, methyl or 2-hydroxyethyl or together with the atoms to which they are attached form an optionally substituted halogen, oxo, -NR¹³R¹⁴Or C₁-C₃Alkyl-substituted azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl rings.

In some embodiments, R¹¹And R¹²Independently hydrogen, methyl or 2-hydroxyethyl.

In some embodiments, R¹³And R¹⁴Independently is hydrogen or C₁-C₃An alkyl group.

In some embodiments, R¹⁵Is hydrogen, halogen, -CN, -OR¹⁸、-NR¹⁸R¹⁹、C₁-C₃Alkyl radical, C₁-C₃Alkenyl radical C₁-C₃Alkynyl or C₃-C₆Cycloalkyl, wherein R¹⁵Optionally substituted by halogen, oxo, CN or-NR¹⁸R¹⁹And (4) substitution.

In some embodiments, R¹⁵Is hydrogen, -CN, halogen or C₁-C₃Alkyl, optionally substituted by halogen, oxo or-NR¹⁸R¹⁹And (4) substitution. In some embodiments, R¹⁵Is F, Cl, Br, -CN, -C (O) NH₂Or a methyl group.

In some embodiments, R¹⁵Is hydrogen or halogen. In some embodiments, R¹⁵Is a halogen. In some embodiments, R¹⁵Is F.

In some embodiments, R¹⁶Is hydrogen, C₁-C₃Alkyl radical, C₁-C₃Alkenyl radical, C₁-C₃Alkynyl, C₃-C₆Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein R¹⁶Optionally substituted by halogen, oxo, -CN, -CF₃、-OR¹⁸、-NR¹⁸R¹⁹Or C₁-C₆Alkyl substitution.

In some embodiments, R¹⁶Is hydrogen or C₁-C₃Alkyl, optionally substituted by oxo, (═ NH), -NR¹⁸R¹⁹OR-OR¹⁸And (4) substitution. In some embodiments, R¹⁶Is methyl, ethyl, 2-hydroxyethyl, -CH₂C(O)NH₂、-CH₂(C＝NH)NH₂or-CH₂C(O)OH。

In some embodiments, R¹⁶Is hydrogen or C₁-C₃An alkyl group. In some embodiments, R¹⁶Is methyl.

In some embodiments, R¹⁸And R¹⁹Independently is hydrogen or C₁-C₃An alkyl group.

In some embodiments, R¹Independently of one another is halogen, R⁴is-NH-or NHC (O) -.

In some embodiments, a is CR³(ii) a X is CH; r¹Independently is hydrogen, -OCH₃、-CF₃、-OCF₃、-CH₃Cl or F, wherein two R are¹Cannot be simultaneously hydrogen; r²Is hydrogen; r³Is hydrogen or-CN; r⁴is-NH-, NHC (O) NH-or NHC (O) O-; and R is⁵Is cyclopropyl, optionally substituted by C₁-C₃Alkyl or halogen substitution.

In some embodiments, a is CR³(ii) a X is CH; r¹Independently is hydrogen, -OCH₃、-CF₃、-OCF₃、-CH₃Cl or F, wherein two R are¹Cannot be simultaneously hydrogen; r²Is hydrogen; r³Is hydrogen or-CN; r⁴is-NH-, NHC (O) NH-or NHC (O) O-; and R is⁵Is pyrimidinyl, pyridinyl, pyridazinyl or pyrazinyl, optionally substituted by R¹⁰And (4) substitution.

In some embodiments, R¹Independently is hydrogen or halogen, R⁴is-NHR⁵、-NR⁶C(O)R⁵、-NR⁶C(O)OR⁵or-NR⁶C(O)NR⁷R⁵，R¹⁶Is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, - (C)₀-C₃Alkyl) CN, - (C)₁-C₃Alkyl) OR¹⁸、-(C₁-C₃Alkyl) SR¹⁸、-(C₁-C₃Alkyl) NR¹⁸R¹⁹、-(C₁-C₃Alkyl) CF₃、-O(C₁-C₃Alkyl) CF₃、-(C₂-C₃Alkyl) NO₂、-(C₀-C₃Alkyl group C (O) R¹⁸、-(C₀-C₃Alkyl) C (O) OR¹⁸、-(C₀-C₃Alkyl group C (O) NR¹⁸R¹⁹、-(C₀-C₃Alkyl) NR¹⁸C(O)R¹⁹、-(C₀-C₃Alkyl) S (O)_1-2R¹⁸、-(C₀-C₃Alkyl) NR¹⁸S(O)_1-2R¹⁹Or- (C)₀-C₃Alkyl) S (O)_1-2NR¹⁸R¹⁹And R is¹⁸And R¹⁹Is hydrogen or C optionally substituted by halogen or oxo₁-C₃Alkyl, and wherein two R are¹Not simultaneously being hydrogen, and R⁵Is not hydrogen.

In some embodiments, a is CR³(ii) a X is CH; r¹Independently is Cl or F; r²Is hydrogen; r³Is hydrogen or-CN; r⁴is-NH-, NHC (O) NH-or NHC (O) O-; r⁵Is pyrimidinyl, pyridinyl, pyridazinyl or pyrazinyl, optionally substituted by R¹⁰Is substituted, and R¹⁶Is hydrogen or C₁-C₃An alkyl group.

Another embodiment includes compounds of formulae Ia-Ib, or stereoisomers or pharmaceutically acceptable salts thereof, selected from:

2- (2, 6-dichlorophenyl) -N- (pyridin-2-yl) -1H-imidazo [4, 5-c ] pyridin-4-amine;

2- (4- (4- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -6-methylpyrimidin-2-yl) piperazin-1-yl) ethanol;

2- (2, 6-dichlorophenyl) -N- (1H-pyrazol-4-yl) -3H-imidazo [4, 5-c ] -pyridin-4-amine;

n- (6-chloropyrimidin-4-yl) -2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichlorophenyl) -N- (6-morpholinopyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chloro-6-fluorophenyl) -N- (pyrazin-2-yl) -3H-imidazo [4, 5-c ] -pyridin-4-amine;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) thiazole-5-carboxamide;

(1R, 2R) -N- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -2-fluorocyclopropanecarboxamide;

(1S, 2S) -N- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -2-fluorocyclopropanecarboxamide;

n- (2- (2, 6-dichloro-4-cyanophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

1- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -3-methylurea;

n- (2- (2, 6-dichlorophenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

n- (2- (2, 6-dichlorophenyl) -3-methyl-3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

8- (2, 6-dichlorophenyl) -N- (pyrimidin-4-yl) -9H-purin-6-amine;

n- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) cyclopropanecarboxamide;

2- (2, 6-dichlorophenyl) -N- (2, 6-dimethylpyrimidin-4-yl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2, 6-dichlorophenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

2- (2, 6-dichlorophenyl) -N- (pyrimidin-4-yl) -1H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichlorophenyl) -N- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

[2- (2, 6-dichloro-phenyl) -1H-imidazo [4, 5-c ] pyridin-4-yl ] - (2, 6-dimethyl-pyrimidin-4-yl) -amine;

2- (2, 6-dichlorophenyl) -N- (pyrimidin-2-yl) -1H-imidazo [4, 5-c ] -pyridin-4-amine;

2- (2, 6-dichlorophenyl) -N- (pyrazin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichlorophenyl) -N- (pyridazin-3-yl) -1H-imidazo [4, 5-c ] -pyridin-4-amine;

n- (2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c)]Pyridin-4-yl) -3-methyl-iso-pyridineOxazol-5-amine;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -benzamide;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl acetamide;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) propanamide;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -isobutyramide;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) pivaloamide;

2- (4- (6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -2-methylpyrimidin-4-yl) piperazin-1-yl) ethanol;

N⁴- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c)]Pyridin-4-yl) -N⁶，N⁶-dimethylpyrimidine-4, 6-diamine;

N⁴- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c)]Pyridin-4-yl) -N²，N²-dimethylpyrimidine-2, 4-diamine;

2- (2, 6-dichlorophenyl) -N- (2-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichlorophenyl) -N- (4-methylpyridin-2-yl) -3H-imidazo [4, 5-c ] -pyridin-4-amine;

2- (2, 6-dichlorophenyl) -N- (5-methylpyridin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (4- (6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) piperazin-1-yl) ethanol;

2- (2, 6-dichlorophenyl) -N- (4-morpholinopyridin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichlorophenyl) -N- (5-morpholinopyridin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichlorophenyl) -N- (6- (4-methylpiperazin-1-yl) pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -pyrimidin-4-ylamino) ethanol;

2- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) isonicotinonitrile;

6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) nicotinonitrile;

2- (2, 6-dichlorophenyl) -N- (5-methylpyrazin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

5- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrazine-2-carbonitrile;

2- (4- (5- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrazin-2-yl) piperazin-1-yl) ethanol;

2- (2-chloro-6-fluorophenyl) -N- (2, 6-dimethylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -cyclopropanecarboxamide;

2- (2-chloro-6-fluorophenyl) -N- (1H-pyrazol-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chloro-6-fluorophenyl) -N- (pyridin-2-yl) -1H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chloro-6-fluorophenyl) -N- (5-methylpyridin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) isonicotinonitrile;

2- (2-chloro-6-fluorophenyl) -N- (4-methylpyridin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) nicotinonitrile;

2- (2-chloro-6-fluorophenyl) -N- (pyridin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (4- (2- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyridin-4-yl) piperazin-1-yl) ethanol;

2- (2-chloro-6-fluorophenyl) -N- (5-morpholinopyridin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (4- (6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyridin-3-yl) piperazin-1-yl) ethanol;

2- (2-chloro-6-fluorophenyl) -N- (5-methylpyrazin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

5- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrazine-2-carbonitrile;

5- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrazine-2-azomethide acid methyl ester; (wherein, formimidate ═ carbonimid acid)

1- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -3-methylurea;

2- (2-chloro-6-fluorophenyl) -N- (pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chloro-6-fluorophenyl) -N- (6-morpholinopyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (4- (6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) piperazin-1-yl) ethanol;

2- (2-chloro-6-fluorophenyl) -N- (6- (4-methylpiperazin-1-yl) -pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-ylamino) ethanol;

3, 5-dichloro-4- (4- (4-methylpyridin-2-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (2, 6-dimethylpyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (5- (4- (2-hydroxyethyl) piperazin-1-yl) pyridin-2-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (4-morpholinopyridin-2-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (4- (4- (2-hydroxyethyl) piperazin-1-yl) pyridin-2-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (5-morpholinopyridin-2-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (5-methylpyridin-2-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (6-morpholinopyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (6- (4-methylpiperazin-1-yl) pyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (6-methoxypyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

2- (2- (2, 6-dichloro-4-cyanophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) isonicotinonitrile;

6- (2- (2, 6-dichloro-4-cyanophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) nicotinonitrile;

3, 5-dichloro-4- (4- (5-methylthiazol-2-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (4-methylthiazol-2-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (thiazol-2-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (6-methylpyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (6- ((2-hydroxyethyl) (methyl) amino) pyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (6- (pyrrolidin-1-yl) pyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (6- (4-hydroxypiperidin-1-yl) pyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (6- (dimethylamino) pyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

n- (2- (2-chloro-4- (methylsulfonyl) phenyl) -3H-imidazo [4, 5-c ] -pyridin-4-yl) cyclopropanecarboxamide;

2- (2-chloro-4- (methylsulfonyl) phenyl) -N- (2, 6-dimethylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2- (trifluoromethyl) phenyl) -1H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

n- (2, 6-dimethylpyrimidin-4-yl) -2- (2- (trifluoromethyl) phenyl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2- (trifluoromethoxy) phenyl) -1H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

n- (2, 6-dimethylpyrimidin-4-yl) -2- (2- (trifluoromethoxy) phenyl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2, 6-dimethylphenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

2- (2, 6-dimethylphenyl) -N- (2, 6-dimethylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2, 6-bis (trifluoromethyl) phenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

2- (2, 6-bis (trifluoromethyl) phenyl) -N- (2, 6-dimethylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2, 6-difluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

2- (2, 6-difluorophenyl) -N- (2, 6-dimethylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chlorophenyl) -N- (2, 6-dimethylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chlorophenyl) -N- (pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chlorophenyl) -N- (pyrazin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chlorophenyl) -N- (pyridin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chlorophenyl) -N- (1H-pyrazol-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2-chlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

n- (2- (2-chlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) acetamide;

1- (2- (2-chlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -3-methylurea;

cyclopropanecarboxylic acid [2- (2, 6-dichloro-phenyl) -1H-imidazo [4, 5-c ] pyridin-4-yl ] -amide;

(2-chloro-6-methyl-pyrimidin-4-yl) - [2- (2, 6-dichloro-phenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl ] -amine;

[2- (2, 6-dichloro-phenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl ] - (6-morpholin-4-yl-pyridazin-3-yl) -amine;

(1S, 2S) -2-fluoro-cyclopropanecarboxylic acid [2- (2, 6-dichloro-phenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-yl ] -amide;

(1R, 2R) -2-fluoro-cyclopropanecarboxylic acid [2- (2, 6-dichloro-phenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-yl ] -amide;

(1S, 2S) -2-fluoro-cyclopropanecarboxylic acid [2- (2-chloro-6-fluoro-phenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl ] -amide;

(1R, 2R) -2-fluoro-cyclopropanecarboxylic acid [2- (2-chloro-6-fluoro-phenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl ] -amide;

[2- (2, 6-dichloro-phenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl ] - (6-methyl-2-morpholin-4-yl-pyrimidin-4-yl) -amine;

[2- (2, 6-dichloro-phenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (6-methyl-2-morpholin-4-yl-pyrimidin-4-yl) -amine;

2- (2, 6-dichlorophenyl) -N- (6-methyl-2- (trifluoromethyl) pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

(1- (4- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -6-methylpyrimidin-2-yl) pyrrolidin-2, 5-diyl) dimethanol;

2, 2' - (4- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -6-methylpyrimidin-2-ylazaldi-nyl) diethanol;

2- ((4- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -6-methylpyrimidin-2-yl) (methyl) amino) ethanol;

N⁴- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c)]Pyridin-4-yl) -N²，N^2，6-trimethylpyrimidine-2, 4-diamine;

2- (2, 6-chlorophenyl) -N- (2-methoxypyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichlorophenyl) -N- (6-methoxypyridin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

[2- (2-chloro-6-fluoro-phenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl ] - (6-methyl-2-morpholin-4-yl-pyrimidin-4-yl) -amine;

[2- (2, 6-dichloro-phenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (2, 6-dimethyl-pyrimidin-4-yl) -amine;

2- (2, 6-dichlorophenyl) -N-phenyl-3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylcarbamic acid methyl ester;

2- (2, 6-dichlorophenyl) -N- (6-methoxypyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichlorophenyl) -N- (5-morpholinopyrazin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichlorophenyl) -N- (5- (4-methylpiperazin-1-yl) pyrazin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (4- (6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyridin-3-yl) piperazin-1-yl) ethanol;

2- (4- (2- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyridin-4-yl) piperazin-1-yl) ethanol;

2- (2, 6-dichlorophenyl) -N- (pyridin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichlorophenyl) -N- (pyridin-3-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c)]Pyridin-4-yl) -5-methyliso-ylOxazol-3-amine;

2- (2, 6-dichlorophenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

1- (6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) piperidin-4-ol;

2- (2, 6-dichlorophenyl) -N- (6- (1, 1-dioxothiomorpholin-4-yl) pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) thiazol-2-amine;

2- (2, 6-dichlorophenyl) -N- (2-methyl-6-morpholinopyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

N⁴- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c)]Pyridin-4-yl) -N⁶，N^6，2-trimethylpyrimidine-4, 6-diamine;

n- (6- (azetidin-1-yl) -2-methylpyrimidin-4-yl) -2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chloro-6-fluorophenyl) -N- (4-morpholinopyridin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

(2- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyridin-4-yl) methanol;

(6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyridin-3-yl) methanol;

2- ((6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) (methyl) amino) ethanol;

2- (2, 6-dichlorophenyl) -N- (6- (pyrrolidin-1-yl) pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -4-methylthiazol-2-amine;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -5-methylthiazol-2-amine;

2- (4- (6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -2-methylpyrimidin-4-yl) piperazin-1-yl) ethanol;

N⁴- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c)]Pyridin-4-yl) -N⁶，N⁶-dimethylpyrimidine-4, 6-diamine;

2- (2-chloro-6-fluorophenyl) -N- (6-methoxypyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chloro-6-fluorophenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chloro-6-fluorophenyl) -N- (5-morpholinopyrazin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

(2- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyridin-4-yl) methanol;

2- (2-chloro-6-fluorophenyl) -N- (2-methyl-6-morpholinopyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

N⁴- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c)]Pyridin-4-yl) -N⁶，N^6，2-trimethylpyrimidine-4, 6-diamine;

2- (2-chloro-6-fluorophenyl) -N- (6- (pyrrolidin-1-yl) pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

(6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyridin-3-yl) methanol;

1- (6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) piperidin-4-ol;

2- ((6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) (methyl) amino) ethanol;

2- (2-chlorophenyl) -N- (6-methyl-2-morpholinopyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

4- [8- (2, 6-dichloro-phenyl) -7H-purin-6-ylamino ] -pyrimidine-2-carbonitrile;

8- (2, 6-dichlorophenyl) -N- (pyridin-2-yl) -9H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (pyridazin-3-yl) -7H-purin-6-amine;

[8- (2, 6-dichloro-phenyl) -7H-purin-6-yl ] - (2, 6-dimethyl-pyrimidin-4-yl) -amine;

2- (4- {6- [8- (2, 6-dichloro-phenyl) -7H-purin-6-ylamino ] -2-methyl-pyrimidin-4-yl } -piperazin-1-yl) -ethanol;

8- (2-chlorophenyl) -N- (pyridin-2-yl) -7H-purin-6-amine;

8- (2-chlorophenyl) -N- (pyrazin-2-yl) -7H-purin-6-amine;

n- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) isobutyramide;

1- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) -3-methylurea;

8- (2, 6-dichlorophenyl) -N- (pyrazin-2-yl) -7H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (5-morpholinopyridin-2-yl) -7H-purin-6-amine;

2- (4- (6- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyridin-3-yl) piperazin-1-yl) ethanol;

8- (2, 6-dichlorophenyl) -N- (4-morpholinopyridin-2-yl) -7H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (4-methylpyridin-2-yl) -7H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (6-methylpyrimidin-4-yl) -7H-purin-6-amine;

2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) isonicotinonitrile;

8- (2, 6-dichlorophenyl) -N- (5-methylpyridin-2-yl) -7H-purin-6-amine;

6- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) nicotinonitrile;

8- (2, 6-dichlorophenyl) -N- (6-morpholinopyrimidin-4-yl) -9H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (6- (4-methylpiperazin-1-yl) pyrimidin-4-yl) -7H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (5-methylpyrazin-2-yl) -7H-purin-6-amine;

5- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyrazine-2-carbonitrile;

2- (4- (2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyridin-4-yl) piperazin-1-yl) ethanol;

2- (4- (6- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyrimidin-4-yl) piperazin-1-yl) ethanol;

2- (6- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyrimidin-4-ylamino) ethanol;

3, 5-dichloro-4- (6- (pyrimidin-4-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (pyrazin-2-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (pyridazin-3-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (6-methylpyrimidin-4-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (6-morpholinopyrimidin-4-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (6- (4- (2-hydroxyethyl) piperazin-1-yl) pyrimidin-4-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (6- (4-methylpiperazin-1-yl) pyrimidin-4-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (pyridin-2-ylamino) -7H-purin-8-yl) benzonitrile;

n- (8- (2, 6-dichloro-4-cyanophenyl) -9H-purin-6-yl) cyclopropanecarboxamide;

3, 5-dichloro-4- (6- (5-morpholinopyridin-2-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (4-methylpyridin-2-ylamino) -7H-purin-8-yl) benzonitrile;

2- (8- (2, 6-dichloro-4-cyanophenyl) -7H-purin-6-ylamino) isonicotinonitrile;

3, 5-dichloro-4- (6- (6-methoxypyrimidin-4-ylamino) -7H-purin-8-yl) benzonitrile;

8- (2-chloro-6-fluorophenyl) -N- (pyrimidin-4-yl) -7H-purin-6-amine;

8- (2-chloro-6-fluorophenyl) -N- (pyrazin-2-yl) -7H-purin-6-amine;

8- (2-chloro-6-fluorophenyl) -N- (pyridazin-3-yl) -7H-purin-6-amine;

8- (2-chloro-6-fluorophenyl) -N- (pyridin-2-yl) -7H-purin-6-amine;

8- (2-chloro-6-fluorophenyl) -N- (6-methylpyrimidin-4-yl) -7H-purin-6-amine;

8- (2-chloro-6-fluorophenyl) -N- (1H-pyrazol-4-yl) -7H-purin-6-amine;

n- (8- (2-chloro-6-fluorophenyl) -7H-purin-6-yl) iso-isomerOxazol-3-amine;

8- (2-chloro-6-fluorophenyl) -7H-purin-6-ylcarbamic acid methyl ester;

1- (8- (2-chloro-6-fluorophenyl) -7H-purin-6-yl) -3-methylurea;

n- (8- (2-chloro-6-fluorophenyl) -7H-purin-6-yl) cyclopropanecarboxamide;

8- (2-chloro-6-fluorophenyl) -N- (6-morpholinopyrimidin-4-yl) -7H-purin-6-amine;

2- (4- (6- (8- (2-chloro-6-fluorophenyl) -7H-purin-6-ylamino) pyrimidin-4-yl) piperazin-1-yl) ethanol;

8- (2-chloro-6-fluorophenyl) -N- (6-methoxypyrimidin-4-yl) -7H-purin-6-amine;

8- (2, 6-dichlorophenyl) -9-methyl-N-phenyl-9H-purin-6-amine; and

8- (2, 6-dichlorophenyl) -9-methyl-N- (pyridin-4-yl) -9H-purin-6-amine.

1- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -3-methylurea;

8- (2, 6-dichlorophenyl) -N- (pyrimidin-4-yl) -9H-purin-6-amine;

n- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) cyclopropanecarboxamide;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -benzamide;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl acetamide;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) propanamide;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) pivaloamide;

5- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrazine-2-azomethide acid methyl ester;

2- (2-chlorophenyl) -N- (pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chlorophenyl) -N- (pyrazin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chlorophenyl) -N- (pyridin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2-chlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) acetamide;

1- (2- (2-chlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -3-methylurea;

N⁴- (2- (2, 6-dichlorophenyl)) -3H-imidazo [4, 5-c]Pyridin-4-yl) -N²，N^2，6-trimethylpyrimidine-2, 4-diamine;

2- (2, 6-dichlorophenyl) -N- (2-methoxypyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

[2- (2-chloro-6-fluoro-phenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl ] - (6-methyl-2-morpholin-4-yl-pyrimidin-4-yl) -amine; [2- (2, 6-dichloro-phenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (2, 6-dimethyl-pyrimidin-4-yl) -amine;

2- (2, 6-dichlorophenyl) -N-phenyl-3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2, 6-dichlorophenyl)-3H-imidazo [4, 5-c]Pyridin-4-yl) -5-methyliso-ylOxazol-3-amine;

4- [8- (2, 6-dichloro-phenyl) -7H-purin-6-ylamino ] -pyrimidine-2-carbonitrile;

8- (2, 6-dichlorophenyl) -N- (pyridin-2-yl) -9H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (pyridazin-3-yl) -7H-purin-6-amine;

8- (2-chlorophenyl) -N- (pyridin-2-yl) -7H-purin-6-amine;

8- (2-chlorophenyl) -N- (pyrazin-2-yl) -7H-purin-6-amine;

n- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) isobutyramide;

1- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) -3-methylurea;

8- (2, 6-dichlorophenyl) -N- (pyrazin-2-yl) -7H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (5-morpholinopyridin-2-yl) -7H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (4-morpholinopyridin-2-yl) -7H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (4-methylpyridin-2-yl) -7H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (6-methylpyrimidin-4-yl) -7H-purin-6-amine;

2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) isonicotinonitrile;

8- (2, 6-dichlorophenyl) -N- (5-methylpyridin-2-yl) -7H-purin-6-amine;

6- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) nicotinonitrile;

8- (2, 6-dichlorophenyl) -N- (6-morpholinopyrimidin-4-yl) -9H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (5-methylpyrazin-2-yl) -7H-purin-6-amine;

5- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyrazine-2-carbonitrile;

3, 5-dichloro-4- (6- (pyrimidin-4-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (pyrazin-2-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (pyridazin-3-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (pyridin-2-ylamino) -7H-purin-8-yl) benzonitrile;

n- (8- (2, 6-dichloro-4-cyanophenyl) -9H-purin-6-yl) cyclopropanecarboxamide;

3, 5-dichloro-4- (6- (4-methylpyridin-2-ylamino) -7H-purin-8-yl) benzonitrile;

2- (8- (2, 6-dichloro-4-cyanophenyl) -7H-purin-6-ylamino) isonicotinonitrile;

8- (2-chloro-6-fluorophenyl) -N- (pyrimidin-4-yl) -7H-purin-6-amine;

8- (2-chloro-6-fluorophenyl) -N- (pyrazin-2-yl) -7H-purin-6-amine;

8- (2-chloro-6-fluorophenyl) -N- (pyridazin-3-yl) -7H-purin-6-amine;

8- (2-chloro-6-fluorophenyl) -N- (pyridin-2-yl) -7H-purin-6-amine;

8- (2-chloro-6-fluorophenyl) -N- (6-methylpyrimidin-4-yl) -7H-purin-6-amine;

8- (2-chloro-6-fluorophenyl) -N- (1H-pyrazol-4-yl) -7H-purin-6-amine;

n- (8- (2-chloro-6-fluorophenyl) -7H-purin-6-yl) iso-isomerOxazol-3-amine;

8- (2-chloro-6-fluorophenyl) -7H-purin-6-ylcarbamic acid methyl ester;

1- (8- (2-chloro-6-fluorophenyl) -7H-purin-6-yl) -3-methylurea;

n- (8- (2-chloro-6-fluorophenyl) -7H-purin-6-yl) cyclopropanecarboxamide;

8- (2-chloro-6-fluorophenyl) -N- (6-methoxypyrimidin-4-yl) -7H-purin-6-amine;

8- (2, 6-dichlorophenyl) -9-methyl-N-phenyl-9H-purin-6-amine;

8- (2, 6-dichlorophenyl) -9-methyl-N- (pyridin-4-yl) -9H-purin-6-amine;

n-4- (8- (2, 6-dichlorophenyl) -9H-purin-6-yl) pyrimidine-4, 6-diamine;

n- (2- (2, 4, 6-trichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

n- (2- (4- (aminomethyl) -2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

n- (2, 6-dimethylpyrimidin-4-yl) -2- (2, 4, 6-trichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (4- (aminomethyl) -2, 6-dichlorophenyl) -N- (2, 6-dimethylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -2-hydroxyacetamide;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -2- (dimethylamino) acetamide;

n- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclobutanecarboxamide;

(3, 5-dichloro-4- (4- (2, 6-dimethylpyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) phenyl) methanol;

2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylcarbamic acid methyl ester;

2- (2-bromo-6-chlorophenyl) -N- (pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2-bromo-6-chlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

2- (2-bromo-6-fluorophenyl) -N- (pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2-bromo-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

6- (2- (2, 6-dichloro-4-cyanophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidine-4-carbonitrile;

3, 5-dichloro-4- (4- (5-methylpyrazin-2-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (5- (hydroxymethyl) pyridin-2-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

n- (6- (azetidin-1-yl) -2-methylpyrimidin-4-yl) -2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

(6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) methanol;

6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidine-4-carbonitrile;

2- (2, 6-dichlorophenyl) -N- (6- (trifluoromethyl) pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

N²- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c)]Pyridine-4-yl) -N⁵，N⁵-dimethylpyrazine-2, 5-diamine;

(5- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrazin-2-yl) methanol;

(6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) methanol;

6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidine-4-carbonitrile;

2- (2-chloro-6-fluorophenyl) -N- (6- (trifluoromethyl) pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (4- (5- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrazin-2-yl) piperazin-1-yl) ethanol;

N²- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c)]Pyridin-4-yl) -N⁵，N⁵-dimethylpyrazine-2, 5-diamine;

2- (2, 6-dichlorophenyl) -N- (pyrimidin-5-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n-4- (2- (2-chlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -N2, N2-dimethylpyrimidine-2, 4-diamine;

2- (2-chlorophenyl) -N- (2-morpholinopyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

3, 5-dichloro-4- (4- (4- (hydroxymethyl) pyridin-2-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

1- (6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -2-methylpyrimidin-4-yl) azetidin-3-ol;

3, 5-dichloro-4- (4- (6- (3-hydroxypyrrolidin-1-yl) pyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (6-thiomorpholinosulfonylpyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3, 5-dichloro-4- (4- (2-methyl-6-morpholinopyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

n- (6- (azetidin-1-yl) pyrimidin-4-yl) -2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

1- (6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) azetidin-3-ol;

1- (6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) ethane-1, 2-diol;

n- (6- (azetidin-1-yl) pyrimidin-4-yl) -2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

1- (6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) azetidin-3-ol;

2- (2-chloro-6-fluorophenyl) -N- (6-thiomorpholinylsulfonylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

1- (6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) ethane-1, 2-diol;

1- (6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -2-methylpyrimidin-4-yl) azetidin-3-ol;

n-4- (2- (2-chlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -N2, N2, 6-trimethylpyrimidine-2, 4-diamine;

(R) -1- (6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) pyrrolidin-3-ol;

(S) -1- (6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) pyrrolidin-3-ol;

(R) -1- (6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) pyrrolidin-3-ol;

(S) -1- (6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) pyrrolidin-3-ol;

(3, 5-dichloro-4- (4- (6-methylpyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) phenyl) methanol;

2- (4- (aminomethyl) -2, 6-dichlorophenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n4- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) pyrimidine-4, 6-diamine;

n4- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) pyrimidine-4, 6-diamine;

n4- (2- (2, 4, 6-trichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) pyrimidine-4, 6-diamine;

n4- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -N6-methylpyrimidine-4, 6-diamine;

2, 2' - (6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-ylazaldi) diethanol;

2, 2' - (6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-ylazaldi) diethanol;

1-cyclopropyl-3- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) urea;

1- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -3-cyclopropylurea;

2- (2, 6-dichlorophenyl) -N- (6- ((dimethylamino) methyl) pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2, 6-dichloro-4- ((methylamino) methyl) phenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

2- (2, 6-dichloro-4- ((methylamino) methyl) phenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichloro-4- ((methylamino) methyl) phenyl) -N- (2, 6-dimethylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2, 6-dichloro-4- ((dimethylamino) methyl) phenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

2- (2, 6-dichloro-4- ((dimethylamino) methyl) phenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichloro-4- ((dimethylamino) methyl) phenyl) -N- (2, 6-dimethylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (2, 6-dichloro-4- (morpholinomethyl) phenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

2- (2, 6-dichloro-4- (morpholinomethyl) phenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichloro-4- (morpholinomethyl) phenyl) -N- (2, 6-dimethylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (3, 5-dichloropyridin-4-yl) -N- (2, 6-dimethylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (2- (3, 5-dichloropyridin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide;

2- (3, 5-dichloropyridin-4-yl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

(6- (2- (3, 5-dichloropyridin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) methanol;

6- (2- (3, 5-dichloropyridin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidine-4-carbonitrile;

n4- (2- (3, 5-dichloropyridin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-yl) pyrimidine-4, 6-diamine;

4- (4- (6-aminopyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) -3, 5-dichlorobenzonitrile;

(1S, 2R) -N- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -2-fluorocyclopropanecarboxamide;

(1R, 2S) -N- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -2-fluorocyclopropanecarboxamide;

n- (6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) acetamide;

2- (6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) propan-2-ol;

n- (6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) acetamide;

2- (6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) propan-2-ol;

n- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -2- (dimethylamino) acetamide;

2- (2-chloro-5-fluorophenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chloro-3-fluorophenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chloro-6-methylphenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chloro-6-methoxyphenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chloro-6- (trifluoromethyl) phenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 5-dichlorophenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 4-dichlorophenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2-chloro-3-methylphenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 3-dichlorophenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (5-bromo-2-chlorophenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

1- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -3-isopropylurea;

1- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -3-isopropylurea;

1- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -3-ethylurea;

3, 5-dichloro-4- (4- (6- (hydroxymethyl) pyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

3-chloro-4- (4- (6-methylpyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

4-chloro-3- (4- (6-methylpyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzonitrile;

(4-chloro-3- (4- (6-methylpyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) phenyl) methanol;

2- (2-chloro-5- (morpholinomethyl) phenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -2-oxoethylcarbamic acid tert-butyl ester;

3, 5-dichloro-4- (4- (6- (hydroxymethyl) pyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) benzamide;

2- (2, 6-dichloro-4-methylphenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichloro-4- (methylthio) phenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichloro-3-fluorophenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidine-4-carboxamide;

6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -N-methylpyrimidine-4-carboxamide;

(6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) (morpholino) methanone;

6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidine-4-carboxamide;

6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -N-methylpyrimidine-4-carboxamide;

(6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyrimidin-4-yl) (morpholino) methanone;

6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -N-methylpyridazine-3-carboxamide;

(6- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyridazin-3-yl) (morpholino) methanone;

6- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -N-methylpyridazine-3-carboxamide;

3-chloro-2- (3-methyl-4- (6-methylpyrimidin-4-ylamino) -3H-imidazo [4, 5-c ] pyridin-2-yl) phenol;

2- (2-chlorophenyl) -N- (6-methylpyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

3, 5-dichloro-4- (6- (6- (trifluoromethyl) pyrimidin-4-ylamino) -7H-purin-8-yl) benzonitrile;

8- (2, 6-dichlorophenyl) -N- (6- (trifluoromethyl) pyrimidin-4-yl) -7H-purin-6-amine;

6- (8- (2-chloro-6-fluorophenyl) -7H-purin-6-ylamino) pyrimidine-4-carbonitrile;

8- (2-chloro-6-fluorophenyl) -N- (5-methylpyrazin-2-yl) -7H-purin-6-amine;

5- (8- (2-chloro-6-fluorophenyl) -7H-purin-6-ylamino) pyrazine-2-carbonitrile;

8- (2, 6-dichlorophenyl) -9-methyl-N- (pyridin-3-yl) -9H-purin-6-amine;

8- (2-chloro-6-fluorophenyl) -9-methyl-N-phenyl-9H-purin-6-amine;

8- (2-chloro-6-fluorophenyl) -9-methyl-N- (pyridin-4-yl) -9H-purin-6-amine;

4- (6- (6-aminopyrimidin-4-ylamino) -7H-purin-8-yl) -3, 5-dichlorobenzonitrile;

3, 5-dichloro-4- (6- (6-ethylpyrimidin-4-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (6-cyclopropylpyrimidin-4-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (5-ethylpyrazin-2-ylamino) -7H-purin-8-yl) benzonitrile;

3, 5-dichloro-4- (6- (5-ethylpyridin-2-ylamino) -7H-purin-8-yl) benzonitrile;

8- (2, 6-dichlorophenyl) -N- (6- (morpholinomethyl) pyrimidin-4-yl) -7H-purin-6-amine;

(R) -1- (6- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyrimidin-4-yl) ethanol;

(S) -1- (6- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyrimidin-4-yl) ethanol;

5- (8- (2, 6-dichloro-4-cyanophenyl) -7H-purin-6-ylamino) pyrazine-2-carbonitrile;

5- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyrazine-2-carbonitrile;

8- (2, 6-dichlorophenyl) -N- (5- ((methylamino) methyl) pyrazin-2-yl) -7H-purin-6-amine;

3, 5-dichloro-4- (6- (6- (1-hydroxyethyl) pyrimidin-4-ylamino) -7H-purin-8-yl) benzonitrile;

n- (6-methylpyrimidin-4-yl) -8- (2, 4, 6-trichlorophenyl) -7H-purin-6-amine;

n4- (8- (2, 4, 6-trichlorophenyl) -7H-purin-6-yl) pyrimidine-4, 6-diamine;

n4- (8- (2, 6-dichloro-4-methylphenyl) -7H-purin-6-yl) pyrimidine-4, 6-diamine;

8- (2, 6-dichloro-4-methylphenyl) -N- (6-methylpyrimidin-4-yl) -7H-purin-6-amine;

8- (2, 6-dichloro-4-ethynylphenyl) -N- (6-methylpyrimidin-4-yl) -7H-purin-6-amine;

8- (2, 6-dichloro-3-fluorophenyl) -N- (6-methylpyrimidin-4-yl) -7H-purin-6-amine;

n4- (8- (2, 6-dichloro-3-fluorophenyl) -7H-purin-6-yl) pyrimidine-4, 6-diamine;

n4- (8- (2-chloro-6-fluoro-3-methylphenyl) -7H-purin-6-yl) pyrimidine-4, 6-diamine;

8- (2-chloro-6-fluoro-3-methylphenyl) -N- (6-methylpyrimidin-4-yl) -7H-purin-6-amine;

n4- (8- (2-chloro-3, 6-difluorophenyl) -7H-purin-6-yl) pyrimidine-4, 6-diamine;

8- (2-chloro-3, 6-difluorophenyl) -N- (6-methylpyrimidin-4-yl) -7H-purin-6-amine;

n4- (8- (2, 3, 6-trichlorophenyl) -7H-purin-6-yl) pyrimidine-4, 6-diamine;

2- (2-chloro-6-fluorophenyl) -N- (6- (4- (oxetan-3-yl) piperazin-1-yl) pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyridin-4-yl) propan-2-ol;

n4- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) pyridine-2, 4-diamine;

n4- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -6-morpholinopyrimidine-2, 4-diamine;

2- (2, 6-dichlorophenyl) -N- (1, 3-dimethyl-1H-pyrazol-5-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

2- (2, 6-dichlorophenyl) -N- (1-methyl-1H-pyrazol-3-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n- (6- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyrimidin-4-yl) -2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

n4- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) -N6, N6-dimethylpyrimidine-4, 6-diamine;

8- (2, 6-dichlorophenyl) -N- (6- (4- (oxetan-3-yl) piperazin-1-yl) pyrimidin-4-yl) -7H-purin-6-amine;

n- (6- (azetidin-1-yl) pyrimidin-4-yl) -8- (2, 6-dichlorophenyl) -7H-purin-6-amine;

2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) isonicotinic acid methyl ester;

2- (2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyridin-4-yl) propan-2-ol;

4- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) picolinic acid methyl ester;

2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) isonicotinic acid;

(5- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyridin-3-yl) methanol;

6- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyrimidin-4-ol;

n2- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) -1, 3, 5-triazine-2, 4-diamine;

n2- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) pyridine-2, 6-diamine;

4- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) picolinic acid;

8- (2, 6-dichlorophenyl) -N- (5-methyl-1H-pyrazol-3-yl) -7H-purin-6-amine;

n4- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) pyridine-2, 4-diamine;

(2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyridin-4-yl) methanol;

8- (2, 6-dichlorophenyl) -N- (1, 3-dimethyl-1H-pyrazol-5-yl) -7H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (1-methyl-1H-pyrazol-3-yl) -7H-purin-6-amine;

n4- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) -2-morpholinopyrimidine-4, 6-diamine;

1- (4- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyridin-2-yl) ethanone;

2- (4- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyridin-2-yl) propan-2-ol;

5- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) nicotinic acid methyl ester;

n- (6-chloropyrimidin-4-yl) -8- (2, 6-dichlorophenyl) -7H-purin-6-amine;

2- (6- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyridin-2-yl) propan-2-ol;

2- (6-amino-8- (2, 6-dichlorophenyl) -9H-purin-9-yl) ethanol;

2- (8- (2, 6-dichlorophenyl) -6- (4- (hydroxymethyl) pyridin-2-ylamino) -9H-purin-9-yl) ethanol;

n5- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) pyrimidine-4, 5-diamine;

2- (6-amino-8- (2, 6-dichlorophenyl) -9H-purin-9-yl) acetic acid;

2- (6-amino-8- (2, 6-dichlorophenyl) -9-purin-9-yl) acetamide;

2- (6-amino-8- (2, 6-dichlorophenyl) -9H-purin-9-yl) acetamidine;

n4- (8- (2, 6-dichlorophenyl) -9H-purin-6-yl) pyrimidine-4, 5-diamine;

n4- (8- (2, 6-dichlorophenyl) -9H-purin-6-yl) pyrimidine-2, 4-diamine;

n2- (8- (2, 6-dichlorophenyl) -9H-purin-6-yl) pyrimidine-2, 4-diamine;

4-amino-6- (8- (2, 6-dichlorophenyl) -9H-purin-6-ylamino) pyrimidin-2-ol;

n4- (8- (2, 6-dichlorophenyl) -9H-purin-6-yl) -2- (methylthio) pyrimidine-4, 6-diamine;

n- (6- (2-oxa-6-azaspiro [3.3] heptan-6-yl) pyrimidin-4-yl) -8- (2, 6-dichlorophenyl) -9H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (5- (trifluoromethyl) pyridin-2-yl) -9H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (4- (trifluoromethyl) pyridin-2-yl) -9H-purin-6-amine;

6- (8- (2, 6-dichlorophenyl) -9H-purin-6-ylamino) -4-methylnicotinonitrile;

8- (2, 6-dichlorophenyl) -N- (4-fluoropyridin-2-yl) -9H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) -9H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N- (5-fluoropyridin-2-yl) -9H-purin-6-amine;

n4- (8- (2, 6-dichlorophenyl) -9H-purin-6-yl) -2-methylpyrimidine-4, 6-diamine;

1- (6- (8- (2, 6-dichlorophenyl) -9H-purin-6-ylamino) pyridin-3-yl) cyclopropanecarboxylic acid;

n4- (8- (2, 6-dichlorophenyl) -9H-purin-6-yl) pyrimidine-2, 4, 6-triamine;

n- (8- (2, 6-dichlorophenyl) -9H-purin-6-yl) -1H-pyrazolo [3, 4-d ] pyrimidin-4-amine;

2- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) isonicotinamide;

(2- (2- (2-chloro-6-fluorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyridin-4-yl) (pyrrolidin-1-yl) methanone;

(2- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) pyridin-4-yl) (pyrrolidin-1-yl) methanone;

8- (2, 6-dichlorophenyl) -7H-purin-6-amine;

8- (2, 6-dichlorophenyl) -N-methyl-7H-purin-6-amine;

(2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyridin-4-yl) (pyrrolidin-1-yl) methanone;

n- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) acetamide;

2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) isonicotinamide;

2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) isonicotinic acid;

2- (2, 6-dichlorophenyl) -N- (6- (3-fluoroazetidin-1-yl) pyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine;

(6- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyrimidin-4-yl) methanol;

8- (2, 6-dichlorophenyl) -9-methyl-9H-purin-6-amine;

n- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) propionamide;

2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) -N-methylisonicotinamide;

azetidin-1-yl (2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyridin-4-yl) methanone;

(2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) pyridin-4-yl) (3-hydroxyazetidin-1-yl) methanone;

2- (8- (2, 6-dichlorophenyl) -7H-purin-6-ylamino) -N- (1-hydroxy-2-methylpropan-2-yl) isonicotinamide;

[2- (3-amino-pyrazin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-yl ] -pyrimidin-4-yl-amine;

[2- (3-amino-pyridin-2-yl) -3H-imidazo [4, 5-c ] pyridin-4-yl ] -pyrimidin-4-yl-amine;

[2- (3-chloro-pyridin-2-yl) -1H-imidazo [4, 5-c ] pyridin-4-yl ] - (2, 6-dimethyl-pyrimidin-4-yl) -amine;

cyclopropanecarboxylic acid [2- (3-chloro-pyridin-2-yl) -1H-imidazo [4, 5-c ] pyridin-4-yl ] -amide;

[2- (2, 6-dichloro-phenyl) -3-methyl-3H-imidazo [4, 5-c ] pyridin-4-yl ] -pyrimidin-4-yl-amine;

[2- (2, 6-dichloro-phenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-yl ] -pyrimidin-4-yl-amine;

[2- (2-amino-pyridin-3-yl) -1H-imidazo [4, 5-c ] pyridin-4-yl ] - (2, 6-dimethyl-pyrimidin-4-yl) -amine;

2- [8- (2, 6-dichloro-phenyl) -6- (2, 6-dimethyl-pyrimidin-4-ylamino) -purin-9-yl ] -ethanol;

cyclopropanecarboxylic acid [8- (2, 6-dichloro-phenyl) -9- (2-hydroxy-ethyl) -9H-purin-6-yl ] -amide;

(2, 6-dimethyl-pyrimidin-4-yl) - [2- (2, 4, 6-trichloro-phenyl) -1H-imidazo [4, 5-c ] pyridin-4-yl ] -amine;

cyclopropanecarboxylic acid [2- (2, 4, 6-trichloro-phenyl) -1H-imidazo [4, 5-c ] pyridin-4-yl ] -amide;

2- [4- (2, 6-dimethyl-pyrimidin-4-ylamino) -1H-imidazo [4, 5-c ] pyridin-2-yl ] -benzonitrile;

2- {8- (2, 6-dichloro-phenyl) -6- [6- (4-methyl-piperazin-1-yl) -pyrimidin-4-ylamino ] -purin-9-yl } -ethanol;

[2- (2, 6-dichloro-phenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (2, 6-dimethyl-pyrimidin-4-yl) -amine;

[2- (2, 6-dichloro-phenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (4-morpholin-4-yl-pyridin-2-yl) -amine;

[2- (2, 6-dichloro-phenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (6-morpholin-4-yl-pyrimidin-4-yl) -amine;

[ 7-chloro-2- (2, 6-dichloro-phenyl) -1H-imidazo [4, 5-c ] pyridin-4-yl ] - (2, 6-dimethyl-pyrimidin-4-yl) -amine;

cyclopropanecarboxylic acid [ 7-chloro-2- (2, 6-dichloro-phenyl) -1H-imidazo [4, 5c ] pyridin-4-yl ] -amide;

cyclopropanecarboxylic acid [2- (2, 6-dichloro-phenyl) -7-methyl-1H-imidazo [4, 5-c ] pyridin-4-yl ] -amide;

[2- (2, 6-dichloro-phenyl) -7-methyl-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (2, 6-dimethyl-pyrimidin-4-yl) -amine;

[2- (2, 6-dichloro-phenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (6-methyl-pyrimidin-4-yl) -amine;

(6-cyclopropyl-pyrimidin-4-yl) - [2- (2, 6-dichloro-phenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl ] -amine;

[2- (2, 6-dichloro-phenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (6-isopropyl-pyrimidin-4-yl) -amine;

[ 7-bromo-2- (2, 6-chloro-phenyl) -1H-imidazo [4, 5-c ] pyridin-4-yl ] - (2, 6-dimethyl-pyrimidin-4-yl) -amine;

cyclopropanecarboxylic acid [ 7-bromo-2- (2, 6-dichloro-phenyl) -1H-imidazo [4, 5-c ] pyridin-4-yl ] -amide;

[2- (2, 6-dichloro-phenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (5-morpholin-4-yl-pyridin-2-yl) -amine;

[2- (2-chloro-6-fluoro-phenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (6-methyl-pyrimidin-4-yl) -amine;

cyclopropanecarboxylic acid [2- (2-chloro-6-fluoro-phenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl ] -amide;

[2- (2-chloro-6-fluoro-phenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (2, 6-dimethyl-pyrimidin-4-yl) -amine;

[ 7-bromo-2- (2, 6-dichloro-phenyl) -1H-imidazo [4, 5-c ] pyridin-4-yl ] - (6-methyl-pyrimidin-4-yl) -amine;

n- [ 7-bromo-2- (2, 6-dichloro-phenyl) -1H-imidazo [4, 5-c ] pyridin-4-yl ] -pyrimidine-4, 6-diamine;

2- (2, 6-dichloro-phenyl) -4- (6-methyl-pyrimidin-4-ylamino) -1H-imidazo [4, 5-c ] pyridine-7-carbonitrile;

4- [2- (2, 6-dichloro-phenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino ] -1-methyl-1H-pyrimidin-2-one;

[2- (4-amino-2-chloro-6-fluoro-phenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (6-methyl-pyrimidin-4-yl) -amine;

n- [ 7-chloro-2- (2, 6-dichloro-phenyl) -1H-imidazo [4, 5-c ] pyridin-4-yl ] -pyrimidine-4, 6-diamine;

2- (2, 6-dichloro-phenyl) -4- (6-methyl-pyrimidin-4-ylamino) -1H-imidazo [4, 5-c ] pyridine-7-carboxylic acid amide;

[2- (2, 6-dichloro-phenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-yl ] -thiazol-5-yl-amine;

[2- (2, 6-dichloro-phenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (6-methyl-pyrimidin-4-yl) -amine;

4- [2- (2, 6-dichloro-phenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-ylamino ] -pyridin-3-ol;

[2- (2, 6-dichloro-phenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-yl ] - (3-methyl-isothiazol-5-yl) -amine;

4- [2- (2, 6-dichloro-phenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino ] -pyridine-3-carbaldehyde;

n- [2- (2-chloro-3, 6-difluoro-phenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl ] -pyrimidine-4, 6-diamine; and

n- [2- (4-amino-2-chloro-6-fluoro-phenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl ] -pyrimidine-4, 6-diamine.

The compounds of the formulae Ia to Ib may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of formulae Ia to Ib, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures, are intended to form part of the present invention. In addition, the present invention includes all geometric and positional isomers. For example, if the compounds of formulae Ia-Ib contain double or fused rings, the cis-and trans-forms and mixtures thereof are included within the scope of the present invention. Single positional isomers and mixtures of positional isomers of compounds of formulae Ia-Ib, e.g. N-oxidation arising from pyrimidinyl or pyrazolyl (pyrrozolyl) rings, or E and Z forms, e.g. oxime moieties, are also within the scope of the present invention.

In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included as compounds of the present invention. When stereochemistry is illustrated by a solid wedge or dashed line representing a particular configuration, then the stereoisomer is as indicated and defined.

The compounds of the present invention may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the invention as defined by the claims is intended to encompass both solvated and unsolvated forms.

In embodiments, the compounds of formulae Ia-Ib may exist in different tautomeric forms, all of which are encompassed within the scope of the invention as defined by the claims. The terms "tautomer" and "tautomeric form" refer to structural isomers having different energies that can be interconverted through a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.

The invention also includes isotopically-labeled compounds of formulae Ia-Ib, which are identical to those recited herein, but for the fact that one or more atoms are substituted with an atomic species corresponding to that naturally found in natureAtomic substitution of atomic masses or mass numbers different in mass or mass number. All isotopes of any particular atom or element recited are contemplated within the scope of the invention. Exemplary isotopes that can be incorporated into compounds of formulae Ia-Ib include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³²P、³³P、³⁵S、¹⁸F、³⁶Cl、¹²³I and¹²⁵I. some isotopically-labeled compounds of formulae Ia-Ib (e.g. are labeled³H and¹⁴those of C) can be used for compound and/or substance tissue distribution analysis. Tritiated (i.e. by tritiation)³H) And carbon-14 (i.e.¹⁴C) Isotopes are useful for their ease of preparation and detectability. Also, with heavier isotopes such as deuterium (i.e. deuterium)²H) Substitutions may provide some therapeutic benefit resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in some circumstances. Positron-emitting isotopes such as¹⁵O、¹³N、¹¹C and¹⁸f can be used in Positron Emission Tomography (PET) studies to detect substrate receptor occupancy. Isotopically labeled compounds of formulae Ia-Ib can generally be prepared by following procedures analogous to those described in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

Synthesis of TYK2 inhibitor compounds

Compounds of formulae Ia-Ib can be synthesized by the synthetic routes described herein. In some embodiments, methods well known in the chemical arts can be used in addition to or in accordance with the descriptions contained herein. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or can be readily prepared using methods well known to those skilled in the art (e.g., by the methods outlined in Louis F. Fieser and Mary Fieser, Reagents for organic Synthesis, Vol.1-19, Wiley, N.Y. (1967. 1999.), Beilsteins handbuch der organischen Chemistry, 4, autofl.dd. Springer-Verlag, Berlin, including supples (also available from Beilstein on-line databases) or comprehensive heterocyclic Chemistry, editors Katrizky and Rees, Pergamon Press, 1984).

The compounds of formulae Ia-Ib can be prepared individually or as a library of compounds comprising at least 2, e.g. 5-1,000, or 10-100 compounds of formulae Ia-Ib. Libraries of compounds of formulae Ia-Ib can be prepared by a combinatorial "split and mix" approach or by multi-step parallel synthesis using solution phase or solid phase chemistry using methods well known to those skilled in the art. Thus, according to a further aspect of the present invention there is provided a library of compounds comprising at least 2 compounds of formulae Ia-Ib or enantiomers, diastereomers or pharmaceutically acceptable salts thereof.

Protection from functional groups (e.g., primary or secondary amines) may be necessary in intermediates in the preparation of the compounds of the invention. The need for such protection will vary depending on the nature of the remote functional group and the conditions of the preparation process. Suitable amino protecting groups (NH-Pg) include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyloxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting Groups and their use, see t.w. greene, Protective Groups in Organic Synthesis, John Wiley & Sons, new york, 1991.

The compounds of the present invention can be prepared from commercially available starting materials using the general procedures described herein.

For purposes of illustration, reaction schemes 1-8 described below provide routes to the compounds of formulae Ia-Ib of the present invention and key intermediates. For a more detailed description of the individual reaction steps, see the examples section below. One skilled in the art will appreciate that other synthetic routes are available and utilized. Although specific starting materials and reagents are described in the schemes and discussed below, other starting materials and reagents can be substituted to provide various derivatives and/or reaction conditions. In addition, the various compounds prepared by the methods described below may be further varied in light of the present disclosure using conventional compounds well known to those skilled in the art.

Scheme 1 describes methods for preparing compounds 1 and 2, and compounds 1 and 2 can be used in other methods for preparing compounds of the present invention. Three methods are shown for the preparation of compound 2. In the first method (method A), 2-chloropyridine-3, 4-diamine may be coupled with an acid chloride to form a mixture of regioisomers. By POCl₃The amide mixture was treated to give compound 1. When heated with HBr in acetic acid, the chlorine can then be replaced by bromine.

In the second process (process B), 2-chloropyridine-3, 4-diamine may be condensed with an acid in the Presence of Polyphosphoric Acid (PPA). This conversion also hydrolyzes the chloride, providing a hydroxy intermediate, when POBr is used₃Which upon treatment can be converted to bromide 2.

In a third process (process C), 2-chloropyridine-3, 4-diamine can be converted to compound 1 in the presence of an aldehyde and ammonium acetate. When heated with HBr in acetic acid, bromine replaces chlorine to give bromide 2.

Scheme 2 describes a method for converting bromide 2 to provide compounds 3 and 4 via a palladium-catalyzed coupling reaction. Reacting bromide 2 with amide (R)⁵CONH₂) Or amines (R)⁵NH₂) Together under nitrogen, under Pd₂(dba)₃、XantPhos、Cs₂CO₃And 1, 4-bisHeating at 150 ℃ for several hours in the presence of an alkane/DME gives the expected product. The palladium-catalyzed coupling reaction can be carried out in a microwave reactor in a closed tube.

Scheme 3 describes a general method for preparing compound 5, and compound 5 can be used for further methods for preparing compounds of the present invention. In process D, in POCl₃Treatment of 6-chloropyrimidine-4, 5-diamine with an acid chloride in the presence of an acid chloride affords intermediate 5. Alternatively, 6-chloropyrimidine-4, 5-diamine condenses with acid when heated in PPA, as shown in method E. This can be accomplished by hydrolysis of the bromide to give the hydroxy intermediate, which reacts with POCl₃Which when heated together may subsequently be converted to compound 5. In Process F, 6-chloropyrimidine-4, 5-diamine is reacted with FeCl₃Can be converted to compound 5 when heated in ethanol with oxygen.

Scheme 4 describes the preparation of compounds 6 and 7 by a palladium catalyzed reaction using compound 5. Under nitrogen, in Pd₂(dba)₃、XantPhos、Cs₂CO₃And 1, 4-bisReaction of chloride 5 with amide (R) in the Presence of an alkane/DME⁵CONH₂) Or amines (R)⁵NH₂) Heating at 160 ℃ for several hours gave the expected product. The palladium-catalyzed coupling reaction can be carried out in a closed tube, in a microwave reactor.

Scheme 5 shows a general synthetic method for preparing other compounds of the present invention. The bromide 2 can be alkylated with electrophiles to give a mixture of N-substituted imidazoles 8 and 9, which can be carried on to the next step without isolation. The subsequent palladium-catalyzed coupling reaction can be carried out in a closed tube in a microwave reactor. Under nitrogen, in Pd₂(dba)₃、XantPhos、Cs₂CO₃And 1, 4-bisMixture of bromides 8 and 9 with amides (R) in the Presence of an alkane/DME⁵CONH₂) Or amines (R)⁵NH₂) Heating together at 150 ℃ for several hours gives the expected product, which can then be isolated by rpHPLC or SFC.

Scheme 6 shows a general preparation of intermediate 21. Oxidation of 2-Cl pyridine by hydrogen peroxide in TFA affords N-oxide 14, which can be nitrated in concentrated sulfuric acid to afford compound 15. Hydrogenation of 15 affords 4-aminopyridine 16, which can be further nitrated to afford 17. Intermediate 16 is then treated with sulfuric acid to provide compound 18, which can be reduced by hydrogen in the presence of raney nickel to provide diaminopyridine 19. Condensation of 19 with benzaldehyde affords imidazopyridine 20 which, when treated with TMSBr in propionitrile, can be converted to bromide 21.

Scheme 7 describes a general method for preparing compounds 22 and 23 by a palladium catalyzed reaction using bromide 21. In Pd₂(dba)₃、XantPhos、Cs₂CO₃And 1, 4-bisReaction of bromide 21 with amide (R) in the Presence of alkane/DME⁵CONH₂) Or amines (R)⁵NH₂) Heating together at 170 ℃ for several hours gives the expected product 22 or 23. The palladium-catalyzed coupling reaction can be carried out in a microwave reactor in a closed tube.

Scheme 8 shows purine chloro 5 and amine (R) via palladium mediated reaction⁵NH₂) Alternative strategies for coupling (scheme 4). Condensation of 6-chloropyrimidine-4, 5-diamine with an acid in the presence of PPA to produce purin-6-ol, which is reacted with POBr₃Is converted into 24. Displacement of the bromide with sodium methanesulfonate followed by oxidation with oxone (oxone) gave methylsulfone 25. Subsequent reaction with SEMCl affords 26, 26 which reacts favorably with R in the presence of a base (NaH)⁵NH₂Reaction to give 27. Deprotection of 27 with TBAF in refluxing THF afforded final product 7.

It will be appreciated that when appropriate functional groups are present, the compounds of the formulae or intermediates used in their preparation may be further derivatised by one or more standard synthetic methods, using condensation, substitution, oxidation, reduction or cleavage reactions. Specific substitution methods include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation, and coupling procedures.

In various exemplary schemes, it may be advantageous to separate the reaction products from each other and/or from the starting materials. Mixtures of diastereomers may be resolved into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, such as chromatography and/or fractional crystallization. Enantiomers are separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Furthermore, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryl compounds) which are considered to be part of the present invention. Enantiomers can also be separated by chiral HPLC columns.

By resolving racemic mixtures using, for example, methods that form diastereomers with optically active resolving agents, single stereoisomers, such as enantiomers, that are substantially free of their stereoisomers can be obtained (Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C.H., J.Chromatogr., 113 (3): 283) -302 (1975)). The racemic mixture of the chiral compounds of the present invention can be isolated and resolved by any suitable method, including: (1) forming an ionized diastereoisomeric salt with the chiral compound and separating by fractional crystallization or other means; (2) forming a diastereomeric compound with a chiral derivatizing reagent, separating the diastereomers, and converting to pure stereoisomers; and (3) separating the substantially pure or enriched stereoisomers directly under chiral conditions. See: drug Stereochemistry, Analytical Methods and Pharmacology, Irving W.Wainer, ed, Marcel Dekker, Inc., New York (1993).

Diastereomeric salts can be formed by reacting enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α -methyl- β -phenylethylamine (amphetamine), and the like, with asymmetric compounds bearing acidic functional groups such as carboxylic and sulfonic acids. Diastereomeric salts can be introduced for separation by fractional crystallization or ion chromatography. For the separation of optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid can lead to the formation of diastereomeric salts.

Alternatively, the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomer pair (Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994, p. 322). Diastereomeric compounds can be formed by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing agent, such as a menthyl derivative, followed by separation of the diastereomers and hydrolysis to produce the pure or enriched enantiomers. The method for determining optical purity involves: preparing chiral esters of racemic mixtures, such as menthyl esters, e.g., (-) -menthyl chloroformate, or Mosher ester, α -methoxy- α - (trifluoromethyl) phenyl acetate in the presence of a base (Jacob, j.org.chem.47: 4165 (1982)); and analyzing the NMR spectrum for the presence of both atropisomeric enantiomers or diastereomers. According to the method for separating atropisomeric naphthyl-isoquinoline compounds (WO 96/15111), the stable diastereoisomers of atropisomeric compounds can be separated and separated by normal-and reverse-phase chromatography. Racemic mixtures of the two enantiomers can be separated by Chromatography using a chiral stationary phase by method (3) (Chiralliquid Chromatography W.J. Lough eds., Chapman and Hall, New York, (1989); Okamoto, J.of Chromatography r.513: 375-. Enriched or purified enantiomers can be distinguished by methods for distinguishing other chiral molecules having asymmetric carbon atoms, such as optical rotation and circular dichroism.

Pharmaceutical compositions and administration

Another embodiment provides pharmaceutical compositions or medicaments comprising a compound of formulae Ia-Ib and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, the compounds of formula Ia-Ib are formulated at ambient temperature, at an appropriate pH and in the desired degree of purity in admixture with physiologically acceptable carriers (i.e., carriers which are not toxic to the recipient) at dosages and concentrations useful for galenic administration. The pH of the formulation depends primarily on the particular application and the concentration of the compound, but is preferably any value from about 3 to about 8. In one example, compounds of formulae Ia-Ib are formulated in an acetate buffer at pH 5. In another embodiment, the compounds of formulae Ia-Ib are sterile. The compounds may be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

The compositions are formulated, administered and administered in a manner consistent with good medical practice. Factors considered herein include the particular disorder being treated, the particular patient being treated, the clinical condition of the individual patient, the cause of the disorder, the location of substance delivery, the method of administration, the schedule of administration, and other factors known to medical practitioners. The "effective amount" of the compound administered will be governed by such considerations and is the minimum amount required to inhibit TYK2 kinase activity. For example, the amount may be below an amount that is toxic to normal cells or the patient as a whole.

The pharmaceutical composition (or formulation) for use may be packaged in various ways, depending on the method used for pharmaceutical administration. Typically, the article for dispensing comprises a volume having the pharmaceutical formulation stored therein in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cartridges, and the like. The container may also include tamper-proof means to prevent tampering with the contents of the pack. In addition, the container has a label stored thereon that describes the contents of the container. The tag may also include an appropriate warning.

Sustained release formulations can be prepared. Suitable examples of sustained release formulations include semipermeable solid hydrophobic polymer matrices containing compounds of formulae Ia-Ib, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl-methacrylate) or poly (vinyl alcohol)), polylactide, co-esters of L-glutamic acid and γ -ethyl-L-glutamatePolymers, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT^TM(injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D- (-) -3-hydroxybutyric acid.

In one example, a pharmaceutically effective amount of a compound of the invention per dose administered parenterally is about 0.01-100mg/kg patient body weight/day or about 0.1-20mg/kg patient body weight/day, with a typical starting range of the compound used being 0.3-15 mg/kg/day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain from about 5 to 100mg of a compound of the invention.

The compounds of the invention may be administered in any suitable manner including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal administration and, if desired for topical treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

The compounds of the present invention may be administered in any conventional form of administration such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain conventional ingredients of pharmaceutical formulations such as diluents, carriers, pH adjusting agents, sweeteners, fillers and other active agents.

Typical formulations are prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, howardc, et al,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systemsphiladelphia: lippincott, Williams&Wilkins, 2004; gennaro, Alfonsor et al,Remington：The Science and Practice of Pharmacyphiladelphia: lippincott, Williams&Wilkins, 2000; and Rowe, Raymond C.Handbook of Pharmaceutical ExcipientsChicago, PharmaThe logical Press, 2005. The formulations may also contain one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents and other known additives to provide a refined appearance of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or to aid in the preparation of the drug (i.e., medicament).

Examples of suitable oral dosage forms are tablets containing about 25mg, 50mg, 100mg, 250mg or 500mg of a compound of the invention admixed with about 90-30mg of anhydrous lactose, about 5-40mg of croscarmellose sodium, about 5-30mg polyvinylpyrrolidone (PVP) K30 and about 1-10mg of magnesium stearate. The powder ingredients are first mixed together and then mixed with the PVP solution. The resulting composition is dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment. An example of an aerosol formulation may be prepared by dissolving a compound of the invention, for example 5-400mg of the compound, in a suitable buffer solution such as phosphate buffer and adding if necessary a tonicity agent (tonicifier) such as a salt such as sodium chloride. The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

In one embodiment, the pharmaceutical composition further comprises an additional therapeutic agent selected from the group consisting of: antiproliferative agents, anti-inflammatory agents, immunomodulators, neurotropic factors (neurotropic factors), drugs for treating cardiovascular diseases, drugs for treating liver diseases, antiviral agents, drugs for treating vascular disorders, drugs for treating diabetes, or drugs for treating immunodeficiency disorders.

Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of formulae Ia-Ib, or a stereoisomer or pharmaceutically acceptable salt thereof. Another embodiment includes a pharmaceutical composition comprising a compound of formulae Ia-Ib, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Another embodiment includes a pharmaceutical composition for treating an immune or inflammatory disorder comprising a compound of formulae Ia-Ib or stereoisomers or pharmaceutically acceptable salts thereof. Another embodiment includes a pharmaceutical composition for treating psoriasis or inflammatory bowel disease comprising a compound of formulae Ia-Ib or a stereoisomer or pharmaceutically acceptable salt thereof.

Indications and treatment methods

Compounds of formulae Ia-Ib inhibit TYK2 kinase activity. Thus, the compounds of formulae Ia-Ib can be used to reduce inflammation in the tissues and cells of a particular patient. The compounds of the invention are useful for inhibiting TYK2 kinase activity in cells that overexpress TYK2 kinase. Alternatively, compounds of formula Ia-Ib can be used to inhibit TYK2 kinase activity in cells in which the type I interferon, IL-6, IL-10, IL-12 and IL-23 signaling pathways are disrupted or abnormal, for example by binding to TYK2 kinase and inhibiting its activity. More generally, the compounds of formula Ia-Ib are useful for the treatment of immune or inflammatory diseases.

Another embodiment includes a method of treating or lessening the severity of a disease or condition responsive to inhibition of TYK2 kinase activity in a patient. The method comprises the step of administering to the patient a therapeutically effective amount of a compound of formulae Ia-Ib, or a stereoisomer, tautomer, or salt thereof.

In one embodiment, a compound of formula Ia-Ib is administered to a patient in a therapeutically effective amount to treat or reduce the severity of a disease or condition that is responsive to inhibition of TYK2 kinase activity, wherein the compound is at least 15-fold or 10-fold or 5-fold or more selective for inhibiting TYK2 kinase activity over inhibiting the activity of the other various Janus kinases.

Another embodiment includes compounds of formulae Ia-Ib, or stereoisomers, tautomers, or salts thereof, for use in therapy.

Another embodiment includes compounds of formulae Ia-Ib, or stereoisomers, tautomers, or salts thereof, for use in the treatment of an immune or inflammatory disease.

Another embodiment includes compounds of formulae Ia-Ib or stereoisomers, tautomers, or salts thereof for use in the treatment of psoriasis or inflammatory bowel disease.

Another embodiment includes the use of a compound of formulae Ia-Ib, or a stereoisomer, tautomer, or salt thereof, for the treatment of an immune or inflammatory disorder.

Another embodiment includes the use of a compound of formulae Ia-Ib, or a stereoisomer, tautomer, or salt thereof, in the treatment of psoriasis or inflammatory bowel disease.

Another embodiment includes the use of a compound of formulae Ia-Ib, or a stereoisomer, tautomer, or salt thereof, for the preparation of a medicament for the treatment of an immune or inflammatory disease.

Another embodiment includes the use of a compound of formulae Ia-Ib, or a stereoisomer, tautomer, or salt thereof, in the manufacture of a medicament for the treatment of psoriasis or inflammatory bowel disease.

In one embodiment, the disease or disorder is cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, alzheimer's disease, cystic fibrosis, viral disease, autoimmune disease, immune disease, atherosclerosis, restenosis, psoriasis, allergic disease, inflammatory disease, neurological disorders, hormone-related diseases, disorders related to organ transplantation, immunodeficiency disorders, destructive bone disease, proliferative disease, infectious disease, disorders related to cell death, thrombin-induced platelet aggregation, liver disease, pathological immune disorders related to T-cell activation, CNS disorders, or myeloproliferative disorders.

In one embodiment, the disease or disorder is cancer.

In one embodiment, the disease or disorder is an immune disorder.

In one embodiment, the disease is a myeloproliferative disorder.

In one embodiment, the myeloproliferative disorder is polycythemia vera, essential thrombocythemia, myelofibrosis, or Chronic Myelogenous Leukemia (CML).

In one embodiment, the disease is asthma.

In one embodiment, the cancer is breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, genitourinary tract cancer, seminoma, esophageal cancer, laryngeal cancer, gastric cancer, stomach cancer, gastrointestinal cancer, skin cancer, keratoacanthoma, follicular cancer, melanoma, lung cancer, small-cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cancer, colon cancer, pancreatic cancer, thyroid cancer, papillary cancer, bladder cancer, liver cancer, biliary tract cancer, kidney cancer, bone cancer, myeloid disorders, lymphoid disorders, hairy cell cancer, oral and pharyngeal cancer (oral cancer), lip cancer, tongue cancer, oral cancer, salivary gland cancer, pharyngeal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, kidney cancer, prostate cancer, vulval cancer, thyroid cancer, large intestine cancer, endometrial cancer, uterine cancer, brain cancer, central nervous system cancer, peritoneal cancer, hepatocellular carcinoma, or combinations thereof, Head cancer, neck cancer, hodgkin's disease, or leukemia.

In one embodiment, the cardiovascular disease is restenosis, cardiac enlargement, atherosclerosis, myocardial infarction, or congestive heart failure.

In one embodiment, the neurodegenerative disease is alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, huntington's disease, and cerebral ischemia, as well as neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, or hypoxia.

In one embodiment, the inflammatory disease is inflammatory bowel disease, crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, contact dermatitis, or delayed hypersensitivity reactions.

In one embodiment, the autoimmune disease is lupus or multiple sclerosis.

The evaluation of drug-induced immunosuppression by the compounds of the present invention can be performed using in vivo functional assays such as arthritis-inducing rodent models and therapeutic or prophylactic treatment to evaluate disease scores, T cell-dependent antibody responses (TDAR) and delayed-type hypersensitivity (DTH). Other in vivo systems, including murine models with host defense against infection or tumor resistance (Burleson GR, Dean JH and Munson AE. methods in immunobiology, Vol.1. Wiley-Liss, New York, 1995) can be considered to elucidate the nature or mechanism of immunosuppression observed. In vivo test systems can be supplemented by well established in vitro or in vitro functional tests for assessing immunocompetence. These assays can include assays of signaling via one or more Janus kinase pathways in B or T cells or immortalized B or T cell lines in response to mitogens or specific antigens, assays of cell surface markers in response to B or T cell signaling, Natural Killer (NK) cell activity, mast cell degranulation, macrophage phagocytic or killer activity, and neutrophil burst oxidation and/or chemotaxis. In each of these assays, measurements of cytokine production by specific effector cells (e.g., lymphocytes, NK, monocytes/macrophages, neutrophils) can be included. In vitro and in vitro tests can be carried out in preclinical and clinical trials using lymphoid tissues and/or peripheral blood (House RV. "Theory and practice of cytokine assessment in immunological analysis" (1999) Methods 19: 17-27; Hubbard AK. "Effects of xenobiotics on macropathology: evaluation in vision" (1999) Methods; 19: 8-16; Lebrec H et al (2001) biology 158: 25-29).

Collagen-induced arthritis (CIA) using an autoimmune mechanism, which mimics human arthritis, was studied in detail for 6-weeks; rat and mouse models (example 68). Collagen-induced arthritis (CIA) is one of the most common animal models of human Rheumatoid Arthritis (RA). The joint inflammation developed in CIA animals well mimics the inflammation observed in RA patients. Blocking Tumor Necrosis Factor (TNF) is an effective treatment for CIA, just as it is a highly effective treatment in the treatment of RA patients. CIA is mediated by T-cells and antibodies (B-cells). Macrophages are believed to play an important role in mediating tissue damage during disease progression. CIA is caused by immunizing animals with collagen emulsified in Complete Freund's Adjuvant (CFA). It is most often caused in DBA/1 mouse strains, but the disease can also be caused in Lewis rats.

There is good evidence that B-cells play a key role in the pathogenesis of autoimmune and/or inflammatory diseases. Protein-based therapies that deplete B cells, such as Rituxan, are effective against autoantibody driven inflammatory diseases such as rheumatoid arthritis (rasetter et al, (2004) Annu Rev Med 55: 477). CD69 is an early activation marker in leukocytes, including T cells, thymocytes, B cells, NK cells, neutrophils, and eosinophils. CD69 human whole blood assay (example 69) determined the ability of compounds to inhibit CD69 production by B lymphocytes in human whole blood activated by cross-linking IgM and goat F (ab') 2 anti-human IgM.

T-cell dependent antibody response (TDAR) predictive test for immune function testing when the potential immunotoxic effects of a compound need to be investigated. The IgM-Plaque Forming Cell (PFC) assay, which uses Sheep Red Blood Cells (SRBC) as antigen, is a standard assay that is currently widely accepted and validated. TDAR has been shown to be a highly predictable assay in mice for adult exposure immunotoxicity detection based on the US National Toxicology Program (NTP) database (M.I. luster et al (1992) fundam. appl. toxicol.18: 200-. The usefulness of this test comes from the fact that: it is an integral assay involving several important components of the immune response. TDAR relies on the function of the following cellular compartments: (1) antigen presenting cells, such as macrophages or dendritic cells; (2) t-helper cells, which are key roles for response initiation and isotype switching; and (3) B-cells, which are the ultimate effector cells responsible for antibody production. Changes in either compartment, as cited by chemistry, can result in significant changes in the synthetic TDAR (M.P.Holsaple: G.R.Burleson, J.H.dean and A.E.Munson, eds., Modern Methods in immunology, Vol.1, Wiley-Liss Publishers, New York, NY (1995), pp.71-108). Typically, the assay is performed as an ELISA for the determination of soluble antibodies (R.J.Smialowizc et al (2001) Toxicol.Sci.61: 164-175) or as a plaque (or antibody) forming cell assay (L.Guo et al (2002) Toxicol.appl.Pharmacol.181: 219-227) to detect the secretion of antigen specific antibodies by plasma cells. The antigen of choice is either a whole cell (e.g., sheep red blood cells) or a soluble protein antigen (T.Miller et al (1998) Toxicol. Sci.42: 129-135).

The compounds of formulae Ia-Ib may be administered by any route suitable for the disease or condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. For topical immunotherapy, the compound may be administered intralesionally, including by flooding the graft prior to inhibition or by contacting with an inhibitor. It will be appreciated that the preferred route may vary, for example, with the recipient. When the compounds of formulae Ia-Ib are administered orally, they may be formulated with pharmaceutically acceptable carriers or excipients into pills, capsules, tablets and the like. When the compounds of formulae Ia-Ib are administered parenterally, they may be formulated in unit dose injectable forms in pharmaceutically acceptable parenteral vehicles, as described in detail below.

The dose for treating a human patient may be from about 5mg to about 1000mg of a compound of formula Ia-Ib. A typical dose may be from about 5mg to about 300mg of a compound of formula Ia-Ib. The dose may be administered once daily (QD), twice daily (BID), or more frequently, depending on pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxicity factors can affect the dosage and administration regimen. When administered orally, the pills, capsules or tablets may be ingested daily or less frequently for a specific period of time. The protocol may be repeated for a plurality of treatment cycles.

Combination therapy

The compounds of formulae Ia-Ib may be used alone or in combination with other therapeutic agents for the treatment of diseases or disorders described herein, such as immune diseases (e.g. psoriasis or inflammation) or hyperproliferative diseases (e.g. cancer). In some embodiments, the compounds of formulae Ia-Ib are combined in a pharmaceutical combination formulation or dosing regimen as a combination therapy with a second therapeutic compound that has anti-inflammatory or anti-hyperproliferative properties or that is useful in the treatment of inflammation, immune response disorders, or hyperproliferative diseases (such as cancer). The second therapeutic agent may be an NSAID or other anti-inflammatory agent. The second therapeutic agent may be a chemotherapeutic agent. The second therapeutic agent of the pharmaceutical combination formulation or dosing regimen preferably has complementary activity to the compounds of formulae Ia-Ib such that they do not adversely affect each other. Such compounds are suitably present in the combination in an amount effective for the intended purpose. In one embodiment, the compositions of the present invention comprise a compound of formulae Ia-Ib, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, in combination with a therapeutic agent, such as an NSAID.

Accordingly, another embodiment includes a method of treating or lessening the severity of a disease or condition responsive to inhibition of TYK2 kinase in a patient comprising administering to said patient a therapeutically effective amount of a compound of formulae Ia-Ib, and further comprising administering a second therapeutic agent.

The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. Combined administration includes co-administration with separate formulations or a single pharmaceutical formulation and tandem administration in any order, wherein preferably there is a period of time when both (or all) active agents exert their biological activity simultaneously.

Suitable dosages for any of the above co-administered agents are those presently used and may be reduced by the combined action (synergy) of the newly identified agent and the other chemotherapeutic agent or treatment.

The compounds of the invention may also be used in combination with radiotherapy. The phrase "radiotherapy" refers to the application of electromagnetic or particulate radiation in the treatment of tumors. Radiotherapy delivers a sufficiently high radiation dose to the target area that regenerative cells in tumor and normal tissues die. The radiation dose regime is usually determined in terms of radiation absorbed dose (rad), time and fractionation, and must be carefully determined by oncological specialists. The amount of radiation a patient receives will depend on various causes, but the two most important causes are the location of the tumor relative to other important structures or organs of the body, and the extent to which the tumor has spread. Examples of radiotherapeutic agents are provided in Hellman, Principles of Radiation Therapy, Cancer, in Principles I and practice of Oncology, 24875(Devita et al, 4 th Ed., Vol. 1, 1993). Alternative forms of radiotherapy include three-dimensional conformal external beam radiation (three-dimensional conformal external beam radiation), Intensity Modulated Radiotherapy (IMRT), stereotactic radiosurgery, and brachytherapy (interstitial radiotherapy), the latter of which places the radiation source directly as an implant "seed" into the tumor. These alternative treatment modalities deliver a greater dose of radiation to the tumor, which results in enhanced efficacy when compared to standard external beam radiotherapy.

Combination therapy may provide "synergy" and prove "synergistic," i.e., the effect obtained when the active ingredients are used together is greater than the sum of the effects produced by the compounds used alone. When the active ingredients (1) are co-formulated and administered or delivered simultaneously in a combined unit dosage formulation; (2) when delivered alternately or in parallel as separate formulations; or (3) by some other protocol, synergy may be achieved. When delivered in alternation therapy, a synergistic effect may be obtained when the compounds are administered or delivered sequentially, e.g. by different injections in separate syringes. Typically, in alternation therapy, the effective doses of each active ingredient are administered sequentially, i.e. sequentially, whereas in combination therapy, the effective doses of two or more active ingredients are administered together.

In particular embodiments of treatment, the compounds of formulae Ia-Ib, or stereoisomers, geometric isomers, tautomers, solvates, metabolites or pharmaceutically acceptable salts or prodrugs thereof, may be combined with other therapeutic, hormonal or antibody substances such as those described herein as well as with surgical treatment and radiation therapy. Accordingly, the combination therapies of the present invention comprise administering at least one compound of formulae Ia-Ib, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, and using at least one other cancer treatment method or immune disorder method. The amounts of the compounds of formulae Ia-Ib and other pharmaceutically active immunological or chemotherapeutic agents and the relative times of administration will be selected to achieve the desired combined therapeutic effect.

Method of manufacture and article

Another embodiment includes a process for preparing a compound of formula Ia-Ib. The method comprises the following steps: (a) reacting a compound of the formula

Wherein R is halogen or other leaving group and X is as defined for formulas Ia-Ib,

with a compound of the formula,

wherein R' is halogen or other leaving group, R¹、R²And A is as defined in formulas Ia-Ib,

obtaining a compound of the formula:

(b) optionally reacting a compound of the formula with a compound of the formula Lv-R¹⁶Reacting a compound wherein Lv is a leaving group such as halogen,

forming a compound of the formula:

wherein R is¹⁶As defined in formulae Ia-Ib;

(c) reacting the above compound with a compound of formula R⁴-R⁵Reacting the compound to form a compound of formulae Ia-Ib, having the formula:

and

(d) optionally subjecting the above compounds to further functionalization.

Another embodiment includes a kit for treating a disease or disorder responsive to inhibition of TYK2 kinase. The kit comprises:

(a) a first pharmaceutical composition comprising a compound of formulae Ia-Ib; and

(b) instructions for use.

In another embodiment, the kit further comprises:

(c) a second pharmaceutical composition comprising a chemotherapeutic agent.

In one embodiment, the instructions comprise instructions for administering said first and second pharmaceutical compositions simultaneously, sequentially or separately to a patient in need thereof.

In one embodiment, the first and second compositions are contained in separate containers.

In one embodiment, the first and second compositions are contained in the same container.

Containers used include, for example, bottles, vials, syringes, blister packs, and the like. The container may be formed from a variety of materials such as glass or plastic. The container contains a compound of formulae Ia-Ib or a formulation thereof effective to treat the condition, and the container may have a sterile access port (e.g. the container may be an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle). The container comprises a composition comprising at least one compound of formulae Ia-Ib. The label or package insert indicates that the composition is to be used to treat a selected condition, such as cancer. In one embodiment, the label or package insert indicates that a composition comprising a compound of formulae Ia-Ib can be used to treat a disorder. In addition, the label or package insert may indicate that the patient to be treated is a patient suffering from a condition characterized by overactive or irregular kinase activity. The label or package insert may also indicate that the composition can be used to treat other conditions.

Articles of manufacture may comprise (a) a first container having therein a compound of formula Ia-Ib; and (b) a second container having a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a chemotherapeutic agent. The article of manufacture of this embodiment of the invention may also include a package insert indicating: the first and second compounds may be used to treat a patient at risk for a stroke, thrombus, or thrombotic disorder. Alternatively or additionally, the article of manufacture may also include a second (or third) container containing a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. It may also contain other substances desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.

The following examples are included to illustrate the invention. However, it should be understood that: these examples are not limiting to the invention and are intended only to illustrate the method of carrying out the invention. Those skilled in the art will recognize that: the chemical reactions can be readily modified to prepare other compounds of formulae Ia-Ib, and alternative methods of preparing compounds of formulae Ia-Ib are within the scope of the invention. For example, synthesis of non-exemplified compounds of the invention can be successfully accomplished by modifications apparent to those skilled in the art, such as by appropriate protection of interfering groups, by the use of other suitable reagents known in the art in addition to those already described, and/or by routine modification of reaction conditions. Alternatively, it will be appreciated that other reactions disclosed herein or known in the art are suitable for preparing other compounds of the invention.

Biological examples

Compounds of formulae Ia-Ib can be tested for their ability to modulate protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or dual specificity kinases in vitro and in vivo. In vitro assays include biochemical and cell-based assays for determining inhibition of kinase activity. Alternative in vitro assays to quantify the ability of compounds of formula Ia-Ib to bind to a kinase may be determined by radiolabelling a compound of formula Ia-Ib prior to binding, isolating a compound of formula Ia-Ib/kinase complex and determining the amount of radiolabel bound or by performing a competition assay in which a compound of formula Ia-Ib is incubated with a known radiolabelled ligand. These and other useful in vitro assays are well known to those skilled in the art.

In embodiments, the compounds of formula Ia-Ib may be used to control, modulate or inhibit tyrosine kinase activity, such as TYK2 kinase activity, additional serine/threonine kinases, and/or dual specificity kinases. Therefore, they can be used as pharmacological standards for the development of new biological experiments, assays and for the study of new pharmacological substances.

Example A

JAK1, JAK2 and TYK2 inhibition test protocol

Monitoring of JAK 3-derived peptides (Val) fluorescently labeled with 5-carboxyfluorescein at the N-terminus by applying the Caliper LabChip technique (Caliper Life Sciences, Hopkinton, Mass.)-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr) to measure the activity of an isolated JAK1, JAK2 or TYK2 kinase domain. To determine the inhibition constants (K) for examples 1-472_i) Compounds were serially diluted in DMSO and added to 50 μ L of a reagent containing 1.5 nMUK 1, 0.2nM purified JAK2 or 1nM purified TYK2 enzyme, 100mM Hepes pH7.2, 0.015% Brij-35, 1.5uM peptide substrate, 25uM ATP, 10mM MgCl₂4mM DTT to a final DMSO concentration of 2%. The reaction was incubated in 384 well polypropylene microtiter plates at 22 ℃ for 30 minutes and then stopped by the addition of 25. mu.L of EDTA-containing solution (100mM hepes pH7.2, 0.015% Brij-35, 150mM EDTA) to give a final EDTA concentration of 50 mM. After termination of the kinase reaction, the ratio of phosphorylated products was determined as a fraction of total peptide substrate using a Caliper LabChip 3000 according to the manufacturer's instructions. K was then determined using the Morrison tight binding model_iThe value is obtained. Morrison, j.f., biochim, biophysis, acta.185: 269-296 (1969); william, j.w. and Morrison, j.f., meth.enzymol., 63: 437-467(1979).

Example B

JAK3 inhibition test protocol

The activity of the isolated JAK3 kinase domain was measured by monitoring phosphorylation of a peptide derived from JAK3 (Leu-Pro-Leu-Asp-Lys-Asp-Tyr-Val-Arg) fluorescently labeled with 5-carboxyfluorescein at the N-terminus using the Caliper LabChip technology (Caliper Life Sciences, Hopkinton, MA). To determine the inhibition constants (K) for examples 1-472_i) Compounds were serially diluted in DMSO and added to 50 μ L of purified JAK3 enzyme containing 5nM, 100mM hepes pH7.2, 0.015% Brij-35, 1.5 μ M peptide substrate, 5 μ M ATP, 10mM MgCl₂4mM DTT to a final DMSO concentration of 2%. The reaction was incubated in 384 well polypropylene microtiter plates at 22 ℃ for 30 minutes and then stopped by the addition of 25. mu.L of EDTA-containing solution (100mM Hepes pH7.2, 0.015% Brij-35, 150mM EDTA) to give a final EDTA concentration of 50 mM. After termination of the kinase reaction, phosphate was determined as a fraction of total peptide substrate using a Caliper LabChip 3000 according to the manufacturer's instructionsThe ratio of the chemical products. K was then determined using the Morrison tight binding model (Morrison, J.F., Biochim. Biophys. acta.185: 269-296 (1969); William, J.W., and Morrison, J.F., meth.EnzymeL., 63: 437-467(1979))_iThe value is obtained.

Example C

Cell-based pharmacological testing

The activity of compounds 1-472 was determined in a cell-based assay designed to measure Janus kinase dependent signaling. Compounds were serially diluted in DMSO and incubated in 96-well microtiter plates in RPMI media with Set-2 cells expressing the JAK2V617F mutein (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ); Braunschweig, Germany) at 37 ℃ for 1 hour to a final cell density of 10⁵Individual cells/well, final DMSO concentration 0.57%. Compound-mediated effects on STAT5 phosphorylation were then measured in lysates of incubated cells using the Meso Scale Discovery (MSD) technique (Gaithersburg, Maryland) according to the manufacturer's protocol and EC was determined₅₀The value is obtained. Alternatively, serial dilutions of the compounds were added to NK92 cells (American type culture Collection (ATCC); Masnasas, Va.) in RPMI medium in 96-well microtiter plates at a final cell density of 10⁵Individual cells/well, final DMSO concentration 0.57%. Then 10ng/ml final concentration to containing NK92 cells and compounds in the microtiter plate adding human recombinant IL-12 (R)&D systems; minneapolis, MN), plates were incubated for 1 hour at 37 ℃. The compound-mediated effect on STAT4 phosphorylation was then determined in lysates from incubated cells using the Meso Scale Discovery (MSD) technique (Gaithersburg, Maryland) according to the manufacturer's protocol₅₀The value is obtained.

The compounds of examples 1-472 were tested in the above assay and found to have an IC of TYK2 inhibition of less than about 5 μ M₅₀The value is obtained. The compounds of examples 1-28, 30-102, 104-134 and 136-215 were tested in the above test and found to have IC's with TYK2 inhibition of less than about 1 μ M₅₀The value is obtained. In the aboveThe compounds of examples-27, 30-86, 93-95, 97-102, 104, 106-, 114, 116-, 134 and 136-215 were tested in an assay and found to have IC's with TYK2 inhibition of less than about 100nM₅₀The value is obtained.

The activity of some compounds of formulae Ia to Ib in the above test (example A) is given in Table A below.

TABLE A

Example numbering	Tyk2 Ki(nM)
		1	1.7
3	14.5
		5	0.6
6	3.1
		7	7.8
10	2.5
		11	4.9
12	13.3
		13	19.5
14	2.8
		15	8.1
16	2.3
		167	7.2
171	27.2

179	1.5
		197	1.4
208	56
		210	27.8
215	56.5
		439	835
447	0.8

Preparation examples

Abbreviations

CD₃OD tritiated methanol

DCM dichloromethane

DIPEA diisopropylethylamine

DMSO dimethyl sulfoxide

DMF dimethyl formamide

EtOAc ethyl acetate

EtOH ethanol

HCl hydrochloric acid

HM-NHM-N is a modified form of diatomaceous earth

IMS industrial methanol denatured alcohol

MeOH methanol

POCl₃ Phosphorus oxychloride

NaH sodium hydride

Na₂SO₄Sodium sulfate

NaHCO₃Sodium bicarbonate

NaOH sodium hydroxide

Pd(PPh₃)₄Tetrakis (triphenylphosphine) palladium (0)

NEt₃Triethylamine

Pd₂dba₃Tris- (dibenzylideneacetone) dipalladium (0)

Si-SPE prefillSilica gel fast chromatographic column

Si-ISCO prefillSilica gel fast chromatographic column

THF tetrahydrofuran

General experimental conditions

The compounds of the present invention can be prepared from commercially available starting materials using the general procedures described herein. Specifically, 2, 6-dichlorobenzoic acid, 2, 6-dichlorobenzoyl chloride, 2-chloro-6-fluorobenzoic acid, 2, 6-bis (trifluoromethyl) benzoic acid, 2, 6-dimethylbenzoic acid, 2-chloro-4- (methylsulfonyl) benzoic acid, 2-chlorobenzoic acid, 2- (trifluoromethyl) benzoic acid, 2- (trifluoromethoxy) benzoic acid, 2, 6-difluorobenzoic acid were purchased from Aldrich st (louis, MO). 2-chloropyridine-3, 4-diamine was purchased from Synthonix (WestForest, NC). 6-Chloropyrimidine-4, 5-diamine was purchased from Princeton Biomolecular Research (Monmouth Junction, N.J.). All commercially available chemicals, including reagents and solvents, were used as obtained.

High pressure liquid chromatography-mass spectrometry coupled (LCMS) experiments were performed to determine Retention Time (RT) and additional mass ions using one of the following methods, UV detectors for 220nm and 254nm monitoring and mass spectrometry scanning 110-800amu in ESI + ionization mode.

LC/MS method A: column: XBridge C18, 4.6 × 50mm, 3.5 mm; mobile phase: water A (0.01% ammonium), B CH₃CN; gradient: 5% -95% of B in 8.0 min; flow rate: 1.2 mL/min; oven temperature 40 ℃ LC/MS.

The method B comprises the following steps: column: AgilentSD-C18, 2.1 × 30mm, 1.8 um; mobile phase: a water with 0.5% TFA, B CH with 0.5% TFA₃CN, within 8.5 minutes; the flow rate is 0.4 mL/min; the oven temperature was 40 ℃.

LCMS method C: column: XBridge C18, 4.6 × 50mm, 3.5 mm; mobile phase: a Water (0.01% NH)₄HCO₃)，B CH₃CN; gradient: 5% -95% of B in 8.0 min; flow rate: 1.2 mL/min; the oven temperature was 40 ℃.

A Varian Unity Inova (400MHz) spectrometer with a triple resonant 5mm probe was used to record ambient temperature¹H NMR spectrum. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations have been used: br is broad, s is singlet, d is doublet, dd is doublet, t is triplet, q is quartet, and m is multiplet.

Using a Biotage Initiator 60^TMMicrowave experiments were performed using a single mode resonator and dynamic field tuning (dynamic field tuning). Temperatures of 40-250 c can be reached and pressures up to 30 bar can be reached.

Example i

4-bromo-2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c ] pyridine

The method A comprises the following steps:

step 1: to a solution of 2-chloropyridine-3, 4-diamine (2.0g, 13.93mmol), diisopropylethylamine (7.29mL, 41.79mmol) in CH₂Cl₂(100mL) and CH₃To a mixture in CN (10mL) cooled to 0 deg.C was added 2, 6-dichlorobenzoyl chloride (2.92g, 13.93mmol) in portions. Then 50mLCH was added₃CN to dissolve the reaction mixture and warm the reaction to 23 ℃ overnight. The reaction was monitored by LC-MS, indicating complete conversion.

The mixture was concentrated to dryness via rotavap to give a brown residue which was then taken up with POCl₃(10.68g, 69.65mmol) was processed. The reaction mixture was heated to 120 ℃ overnight. The reaction mixture was then cooled to 23 ℃, concentrated by rotavap, and poured carefully and slowly onto ice. With saturated NaHCO₃After neutralization of the aqueous solution to pH 7.0, the mixture was extracted with EtOAc (2X 100mL), washed with brine, and dried over anhydrous Na₂SO₄And (5) drying. Subjecting the crude mixture to silica gel column chromatography with 0-10% CH₂Cl₂Purification with MeOH elution gave the expected product (2.9g, 70% yield).¹H NMR(DMSO-d₆，500MHz)：δ13.75(s，1H)，8.20(m，1H)，7.73-7.65(m，5H).LCMS(ESI)m/z：298.0[M+H⁺]

Step 2: 2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c]A solution of pyridin-4-ol (0.2g, 0.6mmol) and HBr in AcOH (33%, 2mL) was heated to 90 deg.C overnight. The reaction was cooled to room temperature, poured into ice and then K was added₂CO₃The aqueous solution was neutralized to pH 7.0. The mixture was extracted with EtOAc (3X 50mL), washed with brine, and washed with Na₂SO₄And (5) drying. Concentration by rotavap gave the expected product as a pale yellow solid (0.14g, 70% yield).¹H NMR(DMSO-d₆，500MHz)：δ13.78(s，1H)，8.18(m，1H)，7.69(m，4H).LCMS(ESI)m/z：343[M+H⁺]

The method B comprises the following steps:

step 1: a mixture of 2-chloropyridine-3, 4-diamine (2.80g, 19.4mmol), 2, 6-dichlorobenzoic acid (3.71g, 19.4mmol) and polyphosphoric acid (50g) was heated to 190 ℃ with stirring for 3 hours. The mixture was then cooled to ambient temperature and poured into ice/water. By addition of saturated Na₂CO₃Neutralizing the resulting mixture. The crude product was collected by filtration, washed with water and dried to give a brown solid (5.4g, 97% yield).¹H NMR(DMSO-d₆，500MHz)：δ13.08(s，1H)，11.21(s，1H)，7.67-7.58(m，3H)，7.15(m，1H)，6.49(d，J＝7.0Hz，1H).LCMS(ESI)m/z：280.0[M+H⁺]

Step 2: reacting 2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c ] at 70 DEG]Pyridin-4-ol (5.4g, 19.3mmol) was added to POBr₃In solution (20mL) and the resulting mixture was then heated at 110 ℃ for 3 hours. The reaction was cooled to room temperature, poured into ice, and then saturated Na was added₂CO₃To effect neutralization. The precipitate was collected by filtration to give the crude product, which was then purified by column chromatography (EtOAc/hexanes 1: 1) to give the desired product as a pale yellow solid (3.2g, 48% yield).¹HNMR(DMSO-d₆，500MHz)：δ13.78(s，1H)，8.18(m，1H)，7.69(m，4H).LCMS(ESI)m/z：343[M+H⁺]

The method C comprises the following steps:

step 1: to a 250mL round bottom flask with magnetic stirrer was added 2-chloropyridine-3, 4-diamine (1.00g, 6.97mmol), 2, 6-dichlorobenzaldehyde (1.28g, 7.32mmol), and ammonium acetate (537mg, 6.97mmol) in absolute ethanol. The flask was loosely capped and heated to 75 ℃ for 3 days. After completion of the reaction, the solvent was removed in vacuo and the residue was purified by column chromatography with petroleum ether/ethyl acetate (5: 1) to give the expected product as a white solid (900mg, 43% yield).¹H NMR(DMSO-d₆，500MHz)：δ13.75(s，1H)，8.20(m，1H)，7.73-7.65(m，5H).LCMS(ESI)m/z：298.0[M+H⁺]

Step 2: 4-chloro-2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c]A mixture of pyridine (500mg, 1.70mmol) and a 33% solution of HBr in HOAc (5.0mL) was heated to 90 deg.C for 15 hours. The reaction was then cooled to 25 ℃ and poured into ice-water. By K₂CO₃The resulting mixture was neutralized with aqueous solution, the solid collected by filtration, washed with water, and dried in vacuo to give the desired product as a pale yellow solid (400mg, 68% yield).¹H NMR(DMSO-d₆，500MHz)：δ13.78(s，1H)，8.18(m，1H)，7.69(m，4H).LCMS(ESI)m/z：343.0[M+H⁺]。

Example ii

6-chloro-8- (2, 6-dichlorophenyl) -9H-purine

The method D comprises the following steps:

6-chloropyrimidine-4, 5-diamine (200mg, 1.4mmol), 2, 6-dichlorobenzoyl chloride (288mg, 1.4mmol), ammonium chloride (0.44g, 8.4mmol) in POCl₃The mixture in (10mL) was heated to 100 ℃ for 15 hours. The mixture was cooled to room temperature, poured carefully slowly into ice/water and washed with NH₄OH (25%) was neutralized to basic (pH 7-8). The mixture was extracted with EtOAc (3X 50mL), and the organic layer was washed with brine (3X 20mL), over Na₂SO₄Drying and vacuum concentrating. The residue was purified by silica gel column chromatography, eluting with EtOAc and petroleum ether (1: 5) to give the expected product (96mg, 22% yield).¹HNMR(DMSO-d₆，500MHz)：δ14.46(s，1H)，8.83(s，1H)，7.68-7.76(m，3H).LCMS(ESI)m/z：299.4[M+H⁺]。

The method E comprises the following steps:

step 1: a mixture of 6-chloropyrimidine-4, 5-diamine (3g, 20.8mmol), 2, 6-dichlorobenzoic acid (4.33g, 20.8mmol) in polyphosphoric acid (PPA, 20mL) was heated to 190 ℃ for 4 hours. Cooling the mixture toAt room temperature, carefully poured slowly into ice/water and taken over Na₂CO₃Neutralized to alkaline (pH 7-8). The resulting mixture was extracted with EtOAc (3X 100mL) and the organic layer was washed with brine (3X 50mL) and Na₂SO₄Drying and vacuum concentrating. The residue was purified by column chromatography (EA ═ 100%) to give the expected product (2g, 34% yield).¹H NMR(DMSO-d₆，500MHz)：δ13.82(s，0.5H)，13.56(s，0.5H)，12.41(s，0.5H)，12.33(s，0.5H)，12.37(d，J＝38Hz，1H)，8.04(s，1H)，7.60-7.68(m，3H).LCMS(ESI)m/z：281.0[M+H⁺]

Step 2: 8- (2, 6-dichlorophenyl) -9H-purin-6-ol (2.0g, 7.14mmol) in POCl₃(20mL) to 100 ℃ for 15 hours. The solvent was removed in vacuo and the residue was carefully poured into ice/water and washed with NH₄OH (25%) was neutralized to basic (pH 7-8). The resulting mixture was extracted with EtOAc (3X 100mL) and the organic layer was washed with brine (3X 50mL) and Na₂SO₄Drying and vacuum concentrating. The residue was purified by column chromatography (EA ═ 100%) to give the expected product (1.8g, 85% yield).¹HNMR(DMSO-d₆，500MHz)：δ14.46(s，1H)，8.83(s，1H)，7.687.76(m，3H).LCMS(ESI)m/z：299.4[M+H⁺]。

Method F:

to a 500mL flask with condenser was added 6-chloropyrimidine-4, 5-diamine (1.44g, 10.0mmol), 2-chloro-6-fluorobenzaldehyde (1.58g, 10.0mmol) and FeCl₃(81mg, 0.5mmol) followed by the addition of EtOH (100 mL). The mixture was evaporated in vacuo and charged with O₂Three times. Reacting the reactant in O₂The mixture was heated at 85 ℃ for 12 hours. The solvent was then removed in vacuo and the residue was purified by column chromatography (MeOH: CH)₂Cl₂1: 20) to give a yellow solid (4.3g, 73%).¹H NMR(DMSO-d₆，500MHz)：δ14.54(Br，1H)，8.86(s，1H)，7.77(dd，J＝18.0，10.0Hz，1H)，7.64(d，d＝10.5Hz，1H)，7.56(t，J＝11.0Hz，1H).LCMS(ESI)m/z：283.0[M+H⁺]。

Example iii

4-bromo-2- (2, 6-dichlorophenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridine

Step 1: a mixture of 2-chloro-5-fluoropyridine (5.0g, 38mmol) and 12.5mL of 50% hydrogen peroxide in 102mL of trifluoroacetic acid was heated to 70-75 deg.C with stirring until TLC showed no starting material remaining. The reaction mixture was evaporated to dryness in vacuo and co-evaporated twice with toluene (20 mL). The residue was diluted with 20mL of water and 100mL of dichloromethane and neutralized by dropwise addition of 28% ammonium hydroxide solution. The aqueous layer was further extracted with dichloromethane (100mL) and the combined organics were dried, filtered and evaporated. The crude product was purified by silica gel column chromatography (MeOH/CH)₂Cl₂1: 10) to give 2-chloro-5-fluoropyridine-1-oxide (4.2g, yield: 74%)¹H NMR(CDCl3，400MHz)δ8.31(dd，J＝2.0，8.5Hz，1H)，7.49(m，1H)，7.07(m，1H).LCMS(ESI)m/z：149.5[M+H⁺]

Step 2: 2-chloro-5-fluoropyridine-N-oxide (1.65g, 11.0mmol) was gradually added to 22mL of concentrated sulfuric acid. Then 4.7g of potassium nitrate was added with stirring. The reaction mixture was heated to 120 ℃ for 2 hours, cooled to room temperature and carefully poured into 80g of crushed ice. The solution was neutralized by adding 28% ammonium hydroxide dropwise with stirring while maintaining the temperature below 15 ℃ with an ice bath. A pale yellow crystalline precipitate was collected by filtration, washed with ice water, and dried to obtain the intended product (1.2g, yield: 59%).¹H NMR(DMSO-d₆，400MHz)δ9.12(m，1H)，8.70(m，1H).LCMS(ESI)m/z：194.5[M+H⁺]

And step 3: a mixture of 2-chloro-5-fluoro-4-nitropyridine-1-oxide (0.75g, 3.9mmol) and 0.8g Raney nickel in 40mL of anhydrous ethanol was hydrogenated in a Parr hydrogenation unit at 40psi for 3 hours, at which time TLC showed that the starting material had disappeared and a new product was detected. The catalyst was removed by filtration and carefully washed with ethanol (2X 20 mL). The combined filtrates were evaporated in vacuo to give the desired product, 4-amino-2-chloro-5-fluoropyridine (0.25g, yield: 44%).¹H NMR(CDCl₃，400MHz)δ7.95(d，J＝2.0Hz，1H)，6.65(d，J＝6.0Hz，1H)，4.52(br s，2H).LCMS(ESI)m/z：113.4[M+H⁺]。

And 4, step 4: 4-amino-2-chloro-5-fluoropyridine (0.77g, 4.7mmol) was carefully added to 7.5mL of concentrated sulfuric acid with stirring at 0-5 deg.C (ice bath) to give a solution. Potassium nitrate (1.1g, 10mmol) was gradually added to the solution over 10 minutes, at which time the internal temperature was maintained below 5 ℃. The reaction mixture was further stirred at 0-5 ℃ for 1 hour and at room temperature for 10 minutes, at which time TLC showed that all starting material had disappeared and a new product was formed. The mixture was carefully poured onto 30g of crushed ice. The resulting solution was extracted with dichloromethane (2X 20 mL). The combined organics were dried, filtered, and concentrated to give the crude product (0.56g, yield: 61%), which was used in the next step without purification. LCMS (ESI) m/z: 192.6[ M + H⁺]。

And 5: 2-chloro-5-fluoro-4-nitroaminopyridine (560mg, 2.9mmol) was carefully added to 4.5mL of concentrated sulfuric acid. The mixture was stirred at room temperature for 12 hours, at which time TLC showed that the starting material had disappeared and a new product had formed. The mixture was then poured onto 11g of crushed ice with stirring. The resulting solution was mixed with 20mL of dichloromethane and neutralized by dropwise addition of 28% ammonium hydroxide with stirring, at which time the internal temperature was maintained below 5 ℃ in a ice-salt bath. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2X 20 mL). The combined organic extracts were dried over MgSO₄Drying, filtration and concentration in vacuo gave the crude product (450mg, yield: 80%) which was used in the next step without purification. LCMS (ESI) m/z: 192.6[ M + H⁺]。

Step 6: a mixture of 4-amino-2-chloro-5-fluoro-3-nitropyridine (0.45g, 2.3mmol) and 0.6g Raney nickel in 10mL of anhydrous ethanol was hydrogenated in a Parr hydrogenation unit at 36psi for 2 hours, at which time TLC showed the disappearance of starting material. The catalyst was removed by filtration and carefully washed with ethanol (2X 10 mL). The combined filtrates were evaporated in vacuo to give a residue which was purified by silica gel Chromatography (CH)₂Cl₂EtOH, 20: 1) to give the expected product (0.26g, yield: 68%)¹HNMR(DMSO-d₆，400MHz)δ7.45(d，J＝2.0Hz，1H)，5.80(br s，2H)，4.98(br s，2H)。

And 7: to a 50mL round bottom flask with a magnetic stirrer were added absolute ethanol (2mL) and twoTo an alkane (10mL) were added 2-chloro-3, 4-diamino-5-fluoropyridine (200mg, 1.2mmol), 2, 6-dichlorobenzaldehyde (220mg, 1.2mmol) and FeCl₃(10mg, 0.06 mmol). The mixture was heated at 75 ℃ for 10 hours under an oxygen balloon. After the reaction was complete, the solvent was partially removed in vacuo and the residue was poured into ice and saturated K₂CO₃(20 mL). The mixture was extracted with dichloromethane (20 mL). The organic layer was separated and the aqueous layer was extracted again with dichloromethane (20 mL). The combined organic extracts were dried over MgSO₄Drying, filtration and evaporation in vacuo gave the crude product (250mg, yield: 64%) which was used in the next step without purification. LCMS (ESI) m/z: 317.6[ M + H⁺]。

And 8: 4-chloro-7-fluoro-2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c]A mixture of pyridine (250mg, 0.8mmol) and TMSBr (0.2mL, 1.5mmol) in propionitrile (10mL) was heated at 120 ℃ for 12 h. The reaction was then cooled to 23 ℃ and saturated K was poured in₂CO₃Ice water (20 mL). The mixture was extracted with dichloromethane (20 mL). The organic layer was separated, washed with brine (10mL), over MgSO₄Drying, filtering and vacuum evaporating. The crude product was purified by chromatography on silica gel (CH)₂Cl₂MeOH, 10: 1) to give the expected product (240mg, yield: 84 percent)¹H NMR(DMSO-d₆，500MHz)：δ14.42(s，1H)，8.20(d，1H)，7.71(m，3H).LCMS(ESI)m/z：362.1[M+H⁺]。

Example 1

2- (2, 6-dichlorophenyl) -N- (pyridin-2-yl) -1H-imidazo [4, 5-c]Pyridine compound4-bromo-2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c ] amine]Pyridine (20mg, 0.058mmol), pyridin-2-amine (7.1mg, 0.076mmol), Pd₂(dba)₃(1.6mg，0.0040mmol)、XantPhos(0.70mg，0.0010mmol)、Cs₂CO₃(38mg, 0.12mmol) of a mixture in 1, 4-dioxane (1.5mL) and DME (0.50mL) with N₂Degassing for 1 minute. The resulting mixture was irradiated in a microwave reactor at 150 ℃ for 2 hours and cooled to room temperature. The mixture was filtered through celite, the filtrate was concentrated and purified by preparative-HPLC (Gilson GX 281, Shim-packed PRC-ODS250mm X20 mm X2, gradient: CH)₃CN/10mm/L NH₄HCO₃17min) to give the expected product as a white solid (5mg, 24% yield).¹H NMR(MeOH-d₄，500MHz)：δ8.34(d，J＝6.0Hz，1H)，7.90(d，J＝8.0Hz，1H)，7.82(m，2H)，7.55(m，2H)，7.51(m，1H)，7.29(d，J＝8.0Hz，1H)，7.06(m，1H).LC-MS(ESI)m/z：356.1[M+H⁺]。

Example 2

2- (4- (4- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-ylamino) -6-methylpyrimidin-2-yl) piperazin-1-yl) ethanol

Step 1: to a suspension of 2-chloro-6-methylpyrimidin-4-amine (0.300g, 2.08mmol) in ethanol (2.0mL) were added 2- (piperazin-1-yl) ethanol (0.810g, 6.25mmol) and diisopropylethylamine (1.5 mL). The mixture was then heated at 150 ℃ for 3 hours under microwave. After concentration by rotavap, the crude product was purified by silica gel column chromatography (EtOAc/hexanes 1: 1) to give the expected product (0.45g, 90% yield).¹H NMR(DMSO-d₆，500MHz)：δ6.24(s，2H)，5.58(s，1H)，4.43(m，1H)，3.60-3.35(m，6H)，2.40-2.37(m，6H)，2.03(s，3H).LCMS(ESI)m/z：238.2[M+H⁺]

Step 2: the coupling reaction of 4-bromo-2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c ] pyridine with 2- (4- (4-amino-6-methylpyrimidin-2-yl) piperazin-1-yl) ethanol was carried out in the same manner as in example 1.

68mg, 47% yield.¹H NMR(DMSO-d₆，500MHz)：δ13.34(s，1H)，8.35(s，1H)，8.07(d，J＝7.0Hz，1H)，7.66(m，4H)，7.26(m，1H)，4.42(s，1H)，3.68(m，4H)，3.52(t，J＝7.0Hz，2H)，2.40(m，6H)，2.27(m，3H).LCMS(ESI)m/z：499.4[M+H⁺]

Example 3

2- (2, 6-dichlorophenyl) -N- (1H-pyrazol-4-yl) -3H-imidazo [4, 5-c ] -pyridin-4-amine

Step 1: 4-nitro-1H-pyrazole (1.13g, 10mmol), DMAP (0.24g, 2.0mmol), (Boc)₂O (2.0g, 9.0mmol)) in CH₂Cl₂The mixture in (150mL) was stirred at 25 ℃ for 3 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography eluting with EtOAc/petroleum ether (1/6) to give the crude product tert-butyl 4-nitro-1H-pyrazole-1-carboxylate (1.3g, 70% yield).¹H NMR(DMSO-d₆，500MHz)：δ8.78(s，1H)，8.22(s，1H)，1.69(s，9H)。

Step 2: a500 mL flask was charged with 4-nitro-1H-pyrazole-1-carboxylic acid tert-butyl ester (1.15g, 5.00mmol), 10% Pd/C (300mg), followed by MeOH (150 mL). The resulting mixture was heated at 60 ℃ in H₂Stir for 15 hours in a balloon. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc/petroleum ether (1/6), to give the expected product as a yellow solid (0.6g, 62% yield).¹H NMR(DMSO-d₆，500MHz)：δ7.34(s，1H)，7.32(s，1H)，4.40(s，2H)，1.53(s，9H).

Step (ii) of3: adding 4-bromo-2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c ] to a microwave tube]Pyridine (0.050g, 0.15mmol), 4-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester (0.032g, 0.17mmol), Pd₂(dba)₃(0.013g，0.015mmol)、XantPhos(0.017g，0.03mmol)、Cs₂CO₃(0.098g, 0.03mmol) and bisAlkane (1.2 mL). Mixing the mixture with N₂Degassing for 1 minute. The resulting mixture was irradiated in a microwave reactor at 160 ℃ for 2 hours and then cooled to room temperature. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by preparative-HPLC (Gilson GX 281, Shim-packed PRC-ODS250 mm. times.20 mm. times.2, gradient: CH)₃CN/10mm/L NH₄HCO₃17min) to give the expected product (15mg, 15% yield).¹HNMR(MeOD-d₄，500MHz)：δ8.09(s，1H)，7.90(d，J＝5.5Hz，1H)，7.76(s，1H)，7.59(m，3H)，6.97(d，J＝5.5Hz，1H).LCMS(ESI)m/z：345.2[M+H⁺]。

Example 4

N- (6-Chloropyrimidin-4-yl) -2- (2, 6-dichlorophenyl) -3H-imidazo- [4, 5-c ] pyridin-4-amine

Adding 4-bromo-2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c ] to a microwave tube]Pyridine (0.100g, 0.29mmol), 2-chloro-6-isopropylpyrimidin-4-amine (0.034g, 0.26mmol), Pd₂(dba)₃(0.026g，0.029mmol)、XantPhos(0.034g，0.058mmol)、Cs₂CO₃(0.189g, 0.58mmol) and bisAlkane (3 mL). Mixing the mixture with N₂Degassing for 1 minute. Irradiating the obtained mixture in a microwave reactor at 140 deg.C for 1.5 hrAnd then cooled to room temperature. The mixture was filtered, the filtrate was concentrated and purified by silica gel column chromatography with EtOAc/petroleum ether (1: 1.5) to give the expected product (50mg, 44% yield).¹H NMR(MeOH-d₄，500MHz)：δ8.56(s，1H)，8.22(m，1H)，7.66-7.59(m，4H)，7.37(d，J＝5.0Hz，1H).LCMS(ESI)m/z：391.6[M+H⁺]。

Example 5

2- (2, 6-dichlorophenyl) -N- (6-morpholinopyrimidin-4-yl) -3H-imidazo [4, 5-c ] pyridin-4-amine

To N- (6-chloropyrimidin-4-yl) -2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c]To a suspension of pyridin-4-amine (0.080g, 0.20mmol) in ethanol (1.5mL) was added diisopropylethylamine (0.2mL) and morpholine (0.088g, 1.0 mmol). The resulting mixture was heated to 130 ℃ for 30 minutes under microwave. The solvent was removed in vacuo and the residue was purified by preparative-HPLC (Gilson GX 281, Shim-filled PRC-ODS250 mm. times.20 mm. times.2, gradient: CH)₃CN/10mm/L NH₄HCO₃17min) to give the expected product (25mg, 28% yield).¹H NMR(DMSO-d₆，500MHz)：δ13.36(s，1H)，8.38(s，1H)，8.26(s，1H)，8.09(m，1H)，7.88(m，1H)，7.67m，3H)，7.26(s，1H)，3.70(m，4H)，3.56(m，4H).LCMS(ESI)m/z：442.3[M+H⁺]。

Example 6

2- (2-chloro-6-fluorophenyl) -N- (pyrazin-2-yl) -3H-imidazo [4, 5-c ] -pyridin-4-amine

Step 1: by 2-chloro in the same operation as in Process BPreparation of 4-bromo-2- (2-chloro-6-fluorophenyl) -1H-imidazo [4, 5-c starting from pyridine-3, 4-diamine and 2-chloro-6-fluorobenzoic acid]Pyridine. 2.6g, yield in two steps 80%.¹H NMR(DMSO-d₆，500MHz)：δ13.82(s，1H)，8.19(d，J＝5.5Hz，1H)，7.61(m，4H).LCMS(ESI) m/z：326.6[M+H⁺]

Step 2: 4-bromo-2- (2-chloro-6-fluorophenyl) -1H) -imidazo [4, 5-c ] was carried out in the same manner as in example 1]Coupling reaction of pyridine with pyrazin-2-amine. 58mg, 56% yield.¹H NMR(DMSO-d₆，500MHz)：δ9.74(s，1H)，8.91(s，1H)，8.28(m，1H)，8.17(d，J＝2.5Hz，1H)，7.94(d，J＝5.5Hz，1H)，7.53(m，3H)，7.20(d，J＝5.5Hz，1H).LCMS(ESI)m/z：340.7[M+H⁺]。

Example 7

N- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) thiazole-5-carboxamide

Step 1: to a suspension of thiazole-5-carboxylic acid (0.30g, 2.32mmol) in toluene (10mL) was added thionyl chloride (2 mL). The resulting mixture was refluxed for 1.5 hours, then the solvent was removed in vacuo. The residue was dissolved in anhydrous THF (10mL) and NH was then added₃Fill the solution for 10 minutes. The mixture was concentrated in vacuo and washed with toluene to give the crude product (0.23g, yield: 77%).¹H NMR(DMSO-d₆，500MHz)：δ9.21(d，J＝2.0Hz，1H)，8.45(d，J＝2.0Hz，1H)，8.18(s，1H)，7.68(s，1H).LCMS(ESI)m/z：128.15[M+H⁺]。

Step 2: adding 4-bromo-2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c ] to a microwave tube]Pyridine (0.050g, 0.15mmol), thiazole-5-carboxamide (0.036g, 0.28mmol), Pd₂(dba)₃(0.013g，0.015mmol)、XantPhos(0.034g，0.03mmol)、Cs₂CO₃(0.098g, 0.3mmol) and bisAlkane (1.2 mL). Mixing the mixture with N₂Degassing for 1 minute. The resulting mixture was irradiated in a microwave reactor at 150 ℃ for 1 hour and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative-HPLC (Gilson GX 281, Shim-filled PRC-ODS250mm X20 mm X2, gradient: CH)₃CN/10mm/L NH₄HCO₃17min) to give the expected product (12mg, 14% yield).¹H NMR(DMSO-d₆，500MHz)：δ9.17(s，1H)，8.71(s，1H)，8.10(s，1H)，7.64-7.55(m，3H)，7.52(m，1H).LCMS(ESI)m/z：390.0[M+H⁺]。

Examples 8 and 9

(1R, 2R) and (1S, 2S) -N- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -2-fluorocyclopropanecarboxamide

Step 1: to cis-2-fluorocyclopropanecarboxylic acid (1.32g, 12.7mmol) and Et₃Ethyl chloroformate (2.06g, 19.0mmol) was added dropwise to a 0 ℃ solution of N (1.92g, 19.0mmol) in anhydrous acetone (25 mL). The reaction mixture was then stirred at room temperature for 1 hour. The precipitated white solid was then filtered off. To the filtrate was added ammonium hydroxide (7.94g, 63.4 mmol). The mixture was stirred at room temperature overnight. The mixture was then concentrated to a semi-solid, which was triturated with EtOAc to give a mixture of (1R, 2R) and (1S, 2S) -2-fluorocyclopropanecarboxamide as an off-white solid (1.01g, 78% yield).¹HNMR(400MHz，MeOH-d₄)δ4.87-4.79(m，0.5H)，4.70-4.62(m，0.5H)，1.85-1.73(m，1H)，1.61(dtd，J＝22.9，7.1，3.6Hz，1H)，1.07(m，1H)。

Step 2: adding 4-bromo-2- (2, 6-dichlorophenyl) into a microwave test tube) -1H-imidazo [4, 5-c]Pyridine (0.070g, 0.20mmol), cis-2-fluorocyclopropanecarboxamide (0.032g, 0.31mmol), Pd₂(dba)₃(0.018g，0.020mmol)、XantPhos(0.023g，0.04mmol)、Cs₂CO₃(0.163g, 0.50mmol) and bisAlkane (1.2 mL). Mixing the mixture with N₂Degassing for 1 minute. The resulting mixture was irradiated in a microwave reactor at 150 ℃ for 1 hour and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-TLC (EtOAc/PE ═ 1: 1) to give a crude mixture, which was then purified by prep-HPLC (AS-H, with CH)₃OH/0.1% DEA as co-solvent SFC, 10min) to give the two expected products as follows.

First elution peak: 12mg, 16% yield. > 98% ee (3.14min, AS-H, SFC, with CH)₃OH/0.1% DEA as co-solvent, 5min).¹H NMR(MeOH-d₄，500MHz)：δ8.04(d，J＝5.5Hz，1H)，7.49(m，3H)，7.42(d J＝5.5Hz，1H)，4.88-4.74(m，1H)，2.11(m，1H)，1.76(m，1H)，1.19(m，2H).LCMS(ESI)m/z：365.2[M+H⁺]。

Second elution peak: 8mg, 10% yield. > 97% ee (3.75min, AS-H, SFC, with CH)₃OH/0.1% DEA as co-solvent, 5min).¹H NMR(MeOH-d₄，500MHz)：δ8.04(d，J＝5.5Hz，1H)，7.51-7.48(m，3H)，7.42(d，J＝5.5Hz，1H)，4.88(m，1H)，2.11(m，1H)，1.76(m，1H)，1.25-1.12(m，2H).LCMS(ESI) m/z：365.0[M+H⁺]。

Example 10

N- (2- (2, 6-dichloro-4-cyanophenyl) -3H-imidazo [4, 5-c)]Pyridin-4-yl) cyclopropanecarboxamidesStep 1: 4-amino-2, 6-dichlorophenol (100g, 0.56mol) and di-tert-butyl dicarbonate (146g, 0.73mol) were dissolved in dibutyl phthalateIn an alkane (1.5L), the mixture was stirred at 110 ℃ overnight. Evaporation of the solvent gave crude tert-butyl 3, 5-dichloro-4-hydroxyphenylcarbamate (220g), which was used directly in the next step.

Tert-butyl 3, 5-dichloro-4-hydroxyphenylcarbamate (220g, crude) and 2, 6-lutidine (78g, 0.73mol) were dissolved in dichloromethane (2.0L). Trifluoromethanesulfonic anhydride (174g, 0.62mol) was added dropwise at-78 ℃ and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by silica gel column chromatography (petroleum ether/EtOAc 40: 1) to give the expected compound (196g, 84% yield).¹HNMR(CDCl₃)δ7.51(s，2H)，6.60(brs，1H)，1.52(s，9H)。

Step/step 2: 4- (tert-Butoxycarbonylamino) -2, 6-dichlorophenyl trifluoromethanesulfonate (14g, 34mmol), dppp (1.4g, 3.4mmol), Pd (OAc)₂(0.84g, 3.4mol) and Et₃A mixture of N (19.6mL) in MeOH (112mL) and DMF (224mL) was refluxed under carbon monoxide atmosphere (10atm) overnight. The solvent was evaporated and the residue was purified by silica gel column chromatography (petroleum ether/EtOAc 80: 1) to give the expected compound (6.5g, yield 60%).¹H NMR(CDCl₃)δ7.40(s，2H)，6.56(brs，1H)，3.94(s，3H)，1.51(s，9H)。

And step 3: methyl 4- (tert-Butoxycarbonylamino) -2, 6-dichlorobenzoate (65g, 0.49mo1) in H₂SO₄The solution in EtOAc (3N, 20mL) was stirred at room temperature for 2 h. The reaction mixture was filtered and the solid collected to give the product (60g, 92% yield).¹H NMR(DMSO)δ8.40(brs，3H)，6.61(s，2H)，3.80(s，3H)。

And 4, step 4: methyl 4-amino-2, 6-dichlorobenzoate (104g, 0.14mol) was added to concentrated HCl (884mL) in a 5-liter round bottom flask and the mixture was cooled in an ice/alcohol bath. Under vigorous stirring inA solution of sodium nitrite (55.2g, 0.8mol) in water (312mL) was slowly added dropwise at a temperature ranging from-5 ℃ to 0 ℃. After 30 minutes, the mixture was filtered and the filtrate was added to a pre-cooled solution of potassium iodide (352.3g, 2.12mol) with mechanical stirring. A black precipitate appeared with the addition. The mixture was warmed to room temperature and stirred overnight. The mixture was diluted with ethyl acetate (1L) and the organic phase was separated. The aqueous phase was extracted with additional ethyl acetate (1L). With NaHSO₃The saturated solution washed the combined dark organic phases to clear. Through Na₂SO₄After drying and concentration by rotavap, the crude product was further purified by silica gel column chromatography (petroleum ether/EtOAc 50/1) to give the expected product (140g, yield 90%) as a yellow oil.¹H NMR(CDCl₃)δ7.70(s，2H)，3.97(s，3H)。

And 5: methyl 2, 6-dichloro-4-iodobenzoate (46g, 0.14mol) was dissolved in pyridine (1380mL) and water (230 mL). Potassium iodide (37.2g, 0.28mol) was added in one portion. The resulting mixture was heated at 130 ℃ for 30 hours. The solvent was removed. The residue was dissolved in 2N HCl (500mL) and extracted with ethyl acetate (3X 1L). The combined organic phases are passed over Na₂SO₄Dried and concentrated by rotavap. The residue was dissolved in N-methylmorpholine (5mL) and concentrated again. The residue was diluted with 2N HCl (100mL) and extracted with dichloromethane (3X 100 mL). The combined organic phases were dried and concentrated to give the desired product (39g, 88%).¹H NMR(DMSO)δ14.26(brs，1H)，7.99(s，2H)。

Step 6: preparation of 4-bromo-2- (2, 6-dichloro-4-iodophenyl) -3H-imidazo [4, 5-c ] starting from 2-chloropyridine-3, 4-diamine and 2, 6-dichloro-4-iodobenzoic acid, following the procedure of Process B]Pyridine. 13g, two-step yield 40%.¹H NMR(DMSO-d₆，500MHz)：δ13.77(Br、1H)，8.19-8.17(m，3H)，7.70(d，J＝5.0Hz，1H).LCMS(ESI)m/z：469.8[M+H⁺]。

And 7: mixing 4-bromo-2- (2, 6-dichloro-4-iodophenyl) -3H-imidazo [4, 5-c]Pyridine (5.0g, 10.7mmol), Zn (CN)₂(2.5g，21mmol)、Pd(PPh₃)₄(1.1g，0.94mmol) mixture in anhydrous DMF (100mL) was heated to 80 ℃ under a nitrogen atmosphere for 2.5 hours. TLC showed complete conversion. Ethyl acetate (100mL) was added to quench the reaction. After removing insoluble solids by filtration, water (100mL) was added. The resulting mixture was extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with brine, over Na₂SO₄Dried and then concentrated. The residue was purified over silica gel to give the product as a pale yellow solid (2.7g, 67% yield).¹HNMR：(DMSO-d₆，500MHz)：δ14.00(Br，1H)，8.39(s，2H)，8.19(s，1H)，7.74(s，1H).LCMS(ESI)m/z：368.9[M+H⁺]。

And 8: adding 4- (4-bromo-1H-imidazo [4, 5-c) to a microwave tube]Pyridin-2-yl) -3, 5-dichlorobenzonitrile (0.10g, 0.27mmol), cyclopropanecarboxamide (0.069g, 0.81mmol), Pd₂(dba)₃(0.036g，0.040mmol)、XantPhos(0.017g，0.030mmol)、Cs₂CO₃(0.26g, 0.81mmol) and bisAlkane (3.0 mL). Mixing the mixture with N₂Degassing for 10 minutes. The resulting mixture was irradiated in a microwave reactor at 160 ℃ for 2 hours and then cooled to room temperature. The mixture was filtered through celite, the filtrate was concentrated and purified by prep-TLC to give the desired product as a white solid (15mg, 15% yield).¹H NMR(MeOH-d₄，500MHz)：δ7.95(s，2H)，7.54(m，1H)，7.45(m，1H)，1.90(m，1H)，1.23-1.18(m，2H)，1.00-0.88(m，2H).LCMS(ESI)m/z：372.0[M+H⁺]。

Example 11

1- (2- (2, 6-dichlorophenyl) -3H-imidazo [4, 5-c ] pyridin-4-yl) -3-methylurea

Adding 4-bromine into a microwave test tube-2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c]Pyridine (0.050g, 0.15mmol), 1-methylurea (0.031g, 0.3mmol), Pd₂(dba)₃(0.013g，0.015mmol)、XantPhos(0.034g，0.030mmol)、Cs₂CO₃(0.147g, 0.45mmol) and bisAlkane (1.0 mL). Mixing the mixture with N₂Degassing for 1 minute. The resulting mixture was irradiated in a microwave reactor at 150 ℃ for 1 hour and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative-HPLC (Gilson GX 281, Shim-filled PRC-ODS250mm X20 mm X2, gradient: CH)₃CN/10mm/L NH₄HCO₃17min) to give the expected product (21mg, 40% yield).¹H NMR(DMSO-d₆，500MHz)：δ12.70(s，1H)，9.34(s，1H)，8.48(s，1H)，7.97(d，J＝7.0Hz，1H)，7.67(m，3H)，7.26(d，J＝5.5Hz，1H)，2.83(d，J＝5.0Hz，3H).LCMS(ESI)m/z：336.2[M+H⁺]。

Examples 12 and 13

N- (2- (2, 6-dichlorophenyl) -1-methyl-1H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide and

n- (2- (2, 6-dichlorophenyl) -3-methyl-3H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide

Step 1: to 4-bromo-2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c at 23 deg.C]To a solution of pyridine (1.0g, 2.9mmol) in DMF (5mL) was added sodium hydride (0.11g, 4.4 mmol). The mixture was stirred at 23 ℃ for 30 minutes, then iodomethane (0.46g, 3.2mmol) was added in one portion and the mixture was stirred at 23 ℃ overnight. The reaction mixture was quenched with water (50mL) and extracted with ethyl acetate (3X 50 mL). The combined organic phases were washed with brine, over Na₂SO₄Dried and then concentrated. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10: 1) to give the expected product as a mixture (0.65g, 62% yield). LCMS (ESI) m/z: 358.1[ M + H⁺]。

Step 2: the Buchwald coupling reaction was carried out in the same operation as in example 1. The mixture was separated by means of a Chiral SFC (Berger MG2Chiral Technology Prep Column (250X 21.2mm, 5 um; conditions: isoconcentration% methanol, 50mL/min, 100 bar, 40 ℃, 254nm) to give the following two expected products.

35mg, 38% yield.¹H NMR：(DMSO-d₆，500MHz)：δ10.41(s，1H)，8.18(d，J＝5.5Hz，1H)，7.72(m，3H)，7.55(d，J＝5.5Hz，1H)，3.63(s，3H)，2.15(m，1H)，0.80(m，4H).LCMS(ESI)m/z：361.1[M+H⁺]。

3mg, 3% yield.¹H NMR：(DMSO-d₆，400MHz)：δ10.69(s，1H)，8.21(d，J＝5.5Hz，1H)，7.70(m，4H)，3.59(s，3H)，1.94(m，1H)，0.84(m，4H).LCMS(ESI)m/z：361.0[M+H⁺]。

Example 14

8- (2, 6-dichlorophenyl) -N- (pyrimidin-4-yl) -9H-purin-6-amine

Adding 6-chloro-8- (2,6-dichlorophenyl) -9H-purine (0.12g, 0.40mmol), pyrimidine-4-amine (0.048g, 0.48mmol), Pd₂(dba)₃(0.036g，0.040mmol)、XantPhos(0.048g，0.080mmol)、Cs₂CO₃(0.26g, 0.80mmol) and bisAlkane (3.0 mL). Mixing the mixture with N₂Degassing for 10 minutes. The resulting mixture was irradiated in a microwave reactor at 160 ℃ for 2 hours and then cooled to room temperature. The mixture was filtered through celite, the filtrate was concentrated and redissolved in DMF for preparative HPLC (Gilson GX 281, Shim-filled PRC-ODS250mm X20 mm X2, gradient: CH₃CN/10mm/L NH₄HCO₃17min) to give the expected product as a white solid (14mg, 9.8% yield).¹H NMR(DMSO-d₆，500MHz，)：δ13.91(s，1H)，10.37(s，1H)，8.85(s，1H)，8.67(s，1H)，8.64(d，J＝6.0Hz，1H)，8.42(s，1H)，7.65-7.73(m，3H).LCMS(ESI)m/z：358.0[M+H ⁺]。

Example 15

N- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) cyclopropanecarboxamide

6-chloro-8- (2, 6-dichlorophenyl) -9H-purine (0.12g, 0.40mmol), Cyclopropanecarboxamide (0.041g, 0.48mmol), Pd were added to a microwave tube₂(dba)₃(0.036g，0.040mmol)、XantPhos(0.048g，0.080mmol)、Cs₂CO₃(0.260g, 0.80mmol) and bisAlkane (3.0 mL). Mixing the mixture with N₂Degassing for 10 minutes. The resulting mixture was irradiated in a microwave reactor at 160 ℃ for 2 hours and then cooled to room temperature. Filtering the mixture with diatomaceous earth, concentrating the filtrate, and recoveringFor preparative HPLC in DMF (Gilson GX 281, Shim-filled PRC-ODS250mm X20 mm X2, gradient: CH)₃CN/10mm/L NH₄HCO₃17min) to give the expected product as a white solid (12mg, 8.5% yield). 1H NMR (DMSO-d6, 500 MHz): δ 12.42(s, 1H), 11.55(s, 1H), 8.69(s, 1H), 7.60-7.66(m, 3H), 2.17(s, 1H), 0.92-0.96(m, 4H). LCMS (ESI) m/z: 348.1[ M + H +]。

Example 16

2- (2, 6-dichlorophenyl) -N- (2, 6-dimethylpyrimidin-4-yl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-amine

4-bromo-7-fluoro-2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c]Pyridine (50mg, 0.14mmol), 2, 6-dimethylpyrimidin-2-amine (22mg, 0.18mmol), Pd₂(dba)₃(4mg，0.0040mmol)、XantPhos(2mg，0.002mmol)、Cs₂CO₃(90mg, 0.28mmol) in 1, 4-bisMixture in alkane (10mL) and DME (2mL) with N₂Degassing for 1 minute. The resulting mixture was irradiated in a microwave reactor at 170 ℃ for 2 hours and cooled to room temperature. The mixture was filtered through celite, the filtrate was concentrated and purified by preparative-HPLC (Gilson GX 281, Shim-packed PRC-ODS250 mm. times.20 mm. times.2, gradient: CH)₃CN/10mm/L NH₄HCO₃17min) to give the expected product (27mg, yield: 48%).¹H NMR(DMSO-d₆，500MHz)：δ8.30(d，J＝6.0Hz，1H)，7.95(s，1H)，7.61(m，4H)，2.39(s，3H)，2.34(s，3H).LC-MS(ESI)m/z：404.4[M+H⁺]。

Example 17

N- (2- (2, 6-dichlorophenyl) -7-fluoro-1H-imidazo [4, 5-c ] pyridin-4-yl) cyclopropanecarboxamide

4-bromo-7-fluoro-2- (2, 6-dichlorophenyl) -1H-imidazo [4, 5-c]Pyridine (50mg, 0.14mmol), cyclopropylamide (15mg, 0.18mmol), Pd₂(dba)₃(4mg，0.0040mmol)、XantPhos(2mg，0.002mmol)、Cs₂CO₃(90mg, 0.28mmol) in 1, 4-bisMixture in alkane (10mL) and DME (2mL) with N₂Degassing for 1 minute. The resulting mixture was irradiated in a microwave reactor at 170 ℃ for 2 hours and cooled to room temperature. The mixture was filtered through celite, the filtrate was concentrated and purified by preparative-HPLC (Gilson GX 281, Shim-packed PRC-ODS250mm X20 mm X2, gradient: CH)₃CN/10mm/L NH₄HCO₃17min) to give the expected product (17mg, yield: 33%).¹H NMR(DMSO-d₆，500MHz)：δ10.76(s，2H)，8.37(s，1H)，7.60(m，3H)，2.06(m，1H)，1.24(m，2H)，0.81(m，2H).LCMS(ESI)m/z：366.3[M+H⁺]。

Additional examples 18-215 shown in Table 1 can be prepared according to the methods described above. The column titled synthesis method gives the method from scheme 1 or 3 for the preparation of intermediates.

TABLE 1

Example 216

N4- (8- (2, 6-dichlorophenyl) -9H-purin-6-yl) pyrimidine-4, 6-diamine

Step 1: to a 100mL round bottom flask was added 8- (2, 6-dichlorophenyl) -9H-purin-6-ol (1.0g, 3.56mmol), followed by anhydrous acetonitrile (6.34mL), and POBr was added dropwise₃(3.34g, 10.67mmol), the mixture was heated to 150 ℃ for 40 minutes and then cooled to 23 ℃. The mixture was carefully poured into ice water (20mL) and extracted with EtOAc (3X 20 mL). The combined organics were passed over Na₂SO₄Drying, concentration, and purification by silica gel column chromatography (30% EtOAc/petroleum ether) afforded pure 6-bromo-8- (2, 6-dichlorophenyl) -9H-purine (700mg, 57% yield).¹H NMR(DMSO-d₆，400MHz)δ14.51(s，1H)，8.80(s，1H)，7.78-7.69(m，3H).LCMS(ESI)m/z：344.9[M+H⁺]。

Step 2: to a solution of 6-bromo-8- (2, 6-dichlorophenyl) -7H-purine (480mg, 1.4mmol) in DMF (10mL) was added sodium methanesulphenyl (391mg, 5.58 mmol). The reaction mixture was heated at room temperature under N₂Stirred for 16 hours. The mixture was then concentrated. The residue was taken up in chloroformSplit between isopropanol (3/1) and brine. The aqueous layer was extracted four more times with chloroform/isopropanol (3/1). The combined organics were dried (Na)₂SO₄) Filtering, and concentrating. The crude product was purified by silica gel chromatography (30-50% EtOAc/hexanes) to give 8- (2, 6-dichlorophenyl) -6- (methylsulfanyl) -7H-purine as a white solid (368mg, 85% yield).¹H NMR(DMSO-d₆，400MHz)δ13.97(s，1H)，8.77(s，1H)，7.78-7.60(m，3H)，2.69(s，3H).LCMS(ESI)m/z：311.1[M+H⁺]。

And step 3: to a solution of 8- (2, 6-dichlorophenyl) -6- (methylthio) -7H-purine (232mg, 0.75mmol) in DMF (5mL) was added Oxone (1.15g, 1.86 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture is saturated with NH₄Quenched with Cl (20mL) and extracted with EtOAc (3X 20 mL). The combined organics were dried (Na)₂SO₄) Filtered and concentrated to give 8- (2, 6-dichlorophenyl) -6- (methylsulfonyl) -7H-purine as a yellow gel which was used in the next step without purification. LCMS (ESI) m/z: 343.0[ M + H⁺]。

And 4, step 4: to a solution of 8- (2, 6-dichlorophenyl) -6- (methylsulfonyl) -7H-purine (343mg, 1.0mmol) in DMF (5mL) at 0 deg.C was added NaH (60%, in mineral oil, 80mg, 2.0mmol) in one portion. The reaction mixture was warmed to room temperature and stirred for 1.5 hours. The mixture was then cooled to 0 ℃. SEM-Cl (250mg, 1.5mmol) was added. The reaction mixture was warmed to room temperature and stirred for 0.5 h. The reaction was quenched with ice water (20mL) and extracted with EtOAc (3X 20 mL). The combined organics were dried (Na)₂SO₄) Filtering, and concentrating. The crude product was purified by silica gel chromatography (10-40% EtOAc/hexanes) to give 8- (2, 6-dichlorophenyl) -6- (methylsulfonyl) -9- ((2- (trimethylsilyl) ethoxy) methyl) -9H-purine as a white solid (263mg, 56% yield).¹HNMR(CDCl₃，400MHz)δ9.23(s，1H)，7.57(s，3H)，5.65(s，2H)，3.62(s，3H)，3.59-3.53(m，2H)，0.95(dd，J＝9.9，7.0Hz，2H)，0.07(s，9H).LCMS(ESI)m/z：475.1[M+H⁺]。

And 5: to a solution of 4, 6-diaminopyrimidine (33mg, 0.3mmol) in DMF (2mL) was added NaH (60% in mineral oil, 16mg, 0.4mmol) at 0 ℃ in one portion. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was then cooled to 0 ℃. A solution of 8- (2, 6-dichlorophenyl) -6- (methylsulfonyl) -9- ((2- (trimethylsilyl) ethoxy) methyl) -9H-purine (47mg, 0.1mmol) in DMF (0.5mL) was added. The reaction mixture was warmed to room temperature and stirred for 0.5 h. The reaction was quenched with ice water (30mL) and extracted with EtOAc (3X 20 mL). The combined organics were dried (Na)₂SO₄) Filtered and concentrated to give crude N-4- (8- (2, 6-dichlorophenyl) -9- ((2- (trimethylsilyl) ethoxy) methyl) -9H-purin-6-yl) pyrimidine-4, 6-diamine (44mg, 88% yield), which was used in the next step without purification. LCMS (ESI) m/z: 503.2[ M + H⁺]。

Step 6: to a solution of N-4- (8- (2, 6-dichlorophenyl) -9- ((2- (trimethylsilyl) ethoxy) methyl) -9H-purin-6-yl) pyrimidine-4, 6-diamine (44mg, 0.09mmol) in THF (2mL) was added TBAF (700mg, 2.68 mmol). The reaction mixture was heated to reflux for 18 hours. The mixture was cooled to room temperature and partitioned between EtOAc (10mL) and water (10 mL). The aqueous layer was extracted with EtOAc (2X 10 mL). The combined organics were dried (Na)₂SO₄) Filtering, and concentrating. The crude product was purified by preparative-HPLC (Gilson GX 281, Shim-filled PRC-ODS250mm X20 mm X2, gradient: CH₃CN/10mm/L NH₄HCO₃17min) to yield N4- (8- (2, 6-dichlorophenyl) -7H-purin-6-yl) pyrimidine-4, 6-diamine as a white solid (8mg, 24% yield).¹H NMR(CDCl₃，400MHz)δ13.76(s，1H)，8.98-8.76(m，1H)，8.56(s，1H)，8.15(s，1H)，7.76-7.58(m，3H)，7.51(s，1H)，6.81(s，2H).LCMS(ESI)m/z：373.0[M+H⁺]。

Additional examples 217-478 shown in Table 2 were prepared as described above. The column titled synthesis method gives the method from scheme 1 or 3 for the preparation of intermediates.

TABLE 2

Although the invention has been described and illustrated with a certain degree of particularity, it is understood that the present disclosure has been made only by way of example and that numerous changes in the combination and rearrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. Compounds of formulae Ia-Ib:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

a is CR³Or N;

x is CR¹⁵Or N;

R¹⁰independently is hydrogen, oxo, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, - (C)₀-C₃Alkyl) CN, - (C)₀-C₃Alkyl) OR¹¹、-(C₀-C₃Alkyl) SR¹¹、-(C₀-C₃Alkyl) NR¹¹R¹²、-(C₀-C₃Alkyl) CF₃、-(C₀-C₃Alkyl) NO₂、-C＝NH(OR¹¹)、-(C₀-C₃Alkyl group C (O) R¹¹、-(C₀-C₃Alkyl) C (O) OR¹¹、-(C₀-C₃Alkyl group OC (O) R¹¹、-(C₀-C₃Alkyl) OC (O) OR¹¹、-(C₀-C₃Alkyl group C (O) NR¹¹R¹²、-(C₀-C₃Alkyl) NR¹¹C(O)R¹²、-(C₀-C₃Alkyl) NR¹¹C(O)OR¹²、-(C₀-C₃Alkyl group OC (O) NR¹¹R¹²、-(C₀-C₃Alkyl) S (O)_1-2R¹¹、-(C₀-C₃Alkyl) NR¹¹S(O)_1-2R¹²、-(C₀-C₃Alkyl) S (O)_1-2NR¹¹R¹²、-(C₀-C₃Alkyl) (C₃-C₈Cycloalkyl), - (C)₀-C₃Alkyl) (3-10 membered heterocyclyl), - (C)₀-C₃Alkyl) C (O) (3-10 membered heterocyclyl) or- (C₀-C₃Alkyl) phenyl, wherein R¹⁰Independently optionally substituted with: halogen, oxo, -CF₃、-(C₀-C₃Alkyl) OR¹³、-(C₀-C₃Alkyl) NR¹³R¹⁴、-(C₀-C₃Alkyl group C (O) R¹³、-(C₀-C₃Alkyl) S (O)_1-2R¹³3-to 10-membered heterocyclic group or C₁-C₃Alkyl, optionally substituted by oxo, halogen, -NR¹³R¹⁴OR-OR¹³Substitution;

R¹¹And R¹²Together with the atom to which they are attached formIs selected from halogen, oxo, -OR¹³、-NR¹³R¹⁴Or C₁-C₃An alkyl-substituted 3-6 membered heterocyclyl;

R¹⁶is hydrogen,C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, - (C)₀-C₃Alkyl) CN, - (C)₁-C₃Alkyl) OR¹⁸、-(C₁-C₃Alkyl) SR¹⁸、-(C₁-C₃Alkyl) NR¹⁸R¹⁹、-(C₁-C₃Alkyl) CF₃、-O(C₁-C₃Alkyl) CF₃、-(C₂-C₃Alkyl) NO₂、-(C₀-C₃Alkyl group C (O) R¹⁸、-(C₀-C₃Alkyl) C (O) OR¹⁸、-(C₀-C₃Alkyl) C (═ NR)¹⁸)NR¹⁸R¹⁹、-(C₀-C₃Alkyl group C (O) NR¹⁸R¹⁹、-(C₀-C₃Alkyl) NR¹⁸C(O)R¹⁹、-(C₀-C₃Alkyl) S (O)_1-2R¹⁸、-(C₀-C₃Alkyl) NR¹⁸S(O)_1-2R¹⁹、-(C₀-C₃Alkyl) S (O)_1-2NR¹⁸R¹⁹、-(C₀-C₃Alkyl) (C₃-C₆Cycloalkyl), - (C)₀-C₃Alkyl) (3-6 membered heterocyclyl), - (C)₀-C₃Alkyl) (5-6 membered heteroaryl) or- (C)₀-C₃Alkyl) phenyl, wherein R¹⁶Optionally substituted with R¹⁰Substitution;

R²⁰And R²¹Independently hydrogen or optionally oxo, -OH or-NH₂Substituted C₁-C₆An alkyl group;

with the proviso that formulae Ia to Ib include compounds other than:

2- (6-amino-7H-purin-8-yl) phenol;

8- (2, 4-dichlorophenyl) -7H-purin-6-amine;

2- (2, 5-dimethoxyphenyl) -N-methyl-3H-imidazo [4, 5-c ] pyridin-4-amine;

8- (2, 3,5, 6-tetrafluoro-4- (1H-imidazol-1-yl) phenyl) -7H-purin-6-amine; and

8-o-tolyl-7H-purin-6-amine.

2. The compound of claim 1, wherein A is CR³And X is CR¹⁵。

3. The compound of claim 1, wherein A is CR³And X is N.

4. A compound according to any one of claims 1 to 3, wherein R¹Independently of one another is hydrogen, halogen, C₁-C₃Alkyl, -CF₃、-OR⁶、-SR⁶、-OCF₃、-NO₂or-NR⁶R⁷Wherein two R are¹Not both hydrogen, and wherein the alkyl group is optionally substituted by halogen, OR⁶or-NR⁶R⁷And (4) substitution.

5. A compound according to any one of claims 1 to 3, wherein one R is¹Is halogen and the other R¹Is hydrogen, halogen, C₁-C₃Alkyl radical, C₃-C₄Cycloalkyl, -CF₃、-OH、-O(C₁-C₃Alkyl), -SH, -S (C)₁-C₃Alkyl), -OCF₃、-CN、-NO₂、-NHSO₂CH₃、-NHC(O)R⁷or-NR⁶R⁷Wherein said alkyl groupAnd cycloalkyl optionally substituted by halogen, OR⁸、-NR⁸R⁹Or phenyl substitution.

6. The compound of any one of claims 1-5, wherein R²Independently is hydrogen, halogen or optionally substituted by R¹⁰Substituted C₁-C₆An alkyl group. In some embodiments, R²Independently F, C1, Br, -CH₂OH、-CH₂NH₂or-CH₂A morpholino group.

7. The compound of any one of claims 1-6, wherein A is CR³And R³Is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, halogen, - (C)₀-C₃Alkyl) CN, - (C)₀-C₃Alkyl) OR⁸、-(C₀-C₃Alkyl) SR⁸、-(C₀-C₃Alkyl) NR⁸R⁹、-(C₀-C₃Alkyl group C (O) NR⁸R⁹、-(C₀-C₃Alkyl) S (O)_1-2R⁸Or- (C)₀-C₃Alkyl) (3-6 membered heterocyclyl), wherein R³Independently is optionally substituted by R¹⁰And (4) substitution.

8. The compound of any one of claims 1-7, wherein R³Is hydrogen, Cl, F, Br, -CH₃Ethynyl, -NH₂、-CN、-S(O)₂CH₃、-C(O)NH₂、-CH₂NH₂、-CH₂OH、-CH₂NH(CH₃)、-CH₂N(CH₃)₂or-CH₂A morpholino group.

9. The compound of any one of claims 1-6 having the structureThe moiety of formula I is selected from:

wherein the wavy line represents the point of attachment in formula I.

10. The compound of any one of claims 1-9, wherein R⁴is-NH-, -NR⁶C(O)-、-NR⁶C (O) O-or-NR⁶C(O)NR⁷-。

11. The compound of any one of claims 1-9, wherein R⁵Is C optionally substituted by halogen₁-C₆An alkyl group; c optionally substituted by halogen₃-C₆A cycloalkyl group; optionally substituted with R¹⁰Substituted phenyl; or optionally substituted with R¹⁰Substituted 3-10 membered heterocyclyl.

12. The compound of any one of claims 1-10, wherein R⁵Selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CH₂OH、-CH₂N(CH₃)₂、-CH₂NHC(O)OC(CH₃)₃Cyclopropyl, cyclobutyl,Phenyl, phenyl,

13. The compound of claim 1, wherein A is CR³(ii) a X is CH; r¹Independently is hydrogen, -OCH₃、-CF₃、-OCF₃、-CH₃Cl, Br or F, wherein two R are¹Cannot be simultaneously hydrogen; r²Is hydrogen, Cl or F; r³Is hydrogen or-CN; r⁴is-NH-, NHC (O) NH-or-NHC (O) O-; and R⁵Is cyclopropyl optionally substituted by halogen or optionally substituted by R¹⁰Substituted pyrimidinyl, pyridinyl, pyridazinyl or pyrazinyl.

14. The compound of claim 1 selected from the compounds of examples 1-472.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

16. A compound according to any one of claims 1 to 14 for use in therapy.

17. A compound according to any one of claims 1 to 14 for use in the treatment of inflammatory diseases.

18. A compound according to any one of claims 1 to 14 for use in the treatment of psoriasis or inflammatory bowel disease.

19. A process for the preparation of a compound according to any one of claims 1 to 14, which process comprises (a) reacting a compound of the formula

Wherein R is a halogen or a leaving group,

with a compound of the formula,

wherein R' is a halogen or a leaving group,

to obtain the compound of the formula iv,

20. the method of claim 19, further comprising reacting the compound of formula iv with a compound of formula Lv-R¹⁶Reacting a compound, wherein Lv is a leaving group, to form a compound of formula va-vb:

21. the method of claim 20, further comprising reacting a compound of formula va-vb with formula R⁴-R⁵The compounds are reacted to form the compounds of formulae Ia-Ib.

22. The novel compounds, methods and uses substantially as described hereinbefore.