Heterocycle amines and uses thereof

Abstract
Compounds and methods in the fields of chemistry and medicine are disclosed. Some of the disclosed embodiments include compounds, compositions and methods of using heterocycle amines. Some of the disclosed embodiments include heterocycle amines useful to treat inflammatory disorders.
Description
FIELD OF THE INVENTION

Compounds and methods in the fields of chemistry and medicine are disclosed. Some of the disclosed embodiments include compounds, compositions and methods of using heterocycle amines. Some of the disclosed embodiments include heterocycle amines useful to treat inflammatory disorders.


BACKGROUND

The recruitment of immune cells to sites of injury involves the concerted interactions of a large number of soluble mediators. Several cytokines appear to play roles in these processes, for example, IL-1 and TNF. Both cytokines are derived from mononuclear cells and macrophages along with other cell types. Physiologically, they produce many of the same proinflammatory responses, including fever, sleep, anorexia, mobilization and activation of polymorphonuclear leukocytes, induction of cyclooxygenase and lipoxygenase enzymes, increase in adhesion molecule expression, activation of B-cells, T-cells and natural killer cells, and stimulation of production of other cytokines. Other actions include a contribution to the tissue degeneration seen in chronic inflammatory conditions, such as stimulation of fibroblast proliferation, induction of collagenase, etc. They have also been implicated in the process of bone resorption and adipose tissue regulation. Thus, these cytokines play key roles in a large number of pathological conditions, including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, cancer, and sepsis.


The role of IL-1 in inflammation has been demonstrated by the ability of the highly specific IL-1 receptor antagonist protein (IL-1 Ra, or IRAP) to relieve inflammatory conditions. IL-1 treatment of cells induces the formation of a complex consisting of the two IL-1 receptor chains, IL-IR1 and IL-1 RAcP, and the resulting heterodimer recruits an adaptor molecule designated as MyD88. MyD88 binds to a protein designated IRAK (Interleukin-1 Receptor-Associated Kinase). IRAK is subsequently phosphorylated and released from the receptor complex to interact with a tumor necrosis factor receptor-associated factor, TRAF6, which transduces the signal to downstream effector molecules. TRAF6 can trigger the NIK/IKK kinase cascade to activate the transcription factor NF-κB. NF-κB regulates a number of genes that, in turn, regulate immune and inflammatory responses.


Four IRAKs have been identified: IRAK-1, IRAK-2, the monomyeloic cell-specific IRAK-M, also known as IRAK-3, and IRAK-4. IRAK proteins have been shown to play a role in transducing signals other than those originating from IL-1 receptors, including signals triggered by activation of IL-18 receptors and LPS receptors. Overexpression of IRAK-2 and IRAK-M has been shown to be capable of reconstituting the response to IL-1 and LPS in an IRAK deficient cell line.


SUMMARY OF THE INVENTION

Compounds, compositions and methods of using heterocycle amines are disclosed. Some of the disclosed embodiments include heterocycle amines useful to treat inflammatory disorders.


Some embodiments include a compound of Formula (I):




embedded image


or a salt, ester, amide, or prodrug thereof,


wherein



custom character is a single or double bond;


W is selected from CH, CH—CH, O, S, NR6, and CO;


Y is N or CR9;


Z is N or C, and Z is N if W is CH and Y is CR9;


R4 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted carbocycle, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, CO2R6, SO3R6, SO2R6 and SO2NR7R8;


R5 is selected from hydrogen, halogen, OR6, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloheteroalkyl, an optionally substituted C1-C6 alkenyl, and an optionally substituted C1-C6 alkynyl;


or R4 and R5 are linked to form an optionally substituted non-aromatic ring;


each R6 is independently selected from an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted non-aromatic ring, each optionally fused with a substituted aryl or a substituted heteroaryl, hydrogen, an optionally substituted C1-C10 alkyl, an optionally substituted C1-C10 haloalkyl, and an optionally substituted C1-C10 heteroalkyl;


each R7 and R8 is independently selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, each optionally fused with a substituted aryl or a substituted heteroaryl, hydrogen, an optionally substituted C1-C10 alkyl, an optionally substituted C1-C10 haloalkyl, an optionally substituted C1-C10 alkenyl, an optionally substituted C1-C10 alkynyl, and an optionally substituted C1-C10 heteroalkyl, or R7 and R8 are linked to form an optionally substituted non-aromatic ring;


R9 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, CO2R6, SO3R6, and SO2NR7R8;


A is an optionally substituted aryl or an optionally substituted heteroaryl group;


each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, heterohaloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic ring, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, ═O, ═S, amino, and protected derivatives of amino groups.


In some embodiments, R4 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted carbocycle, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, CO2R6, SO3R6, SO2R6 and SO2NR7R8


In some embodiments, if R4 is pyrazolyl, the pyrazolyl is not substituted with aryl or heteroaryl groups.


In some embodiments, if R4 is oxazolyl, isoxazolyl, or imidazoyl, the oxazolyl, isoxazolyl, or imidazoyl radical is not substituted with aryl or heteroaryl groups.


Some embodiments include a compound represented by Formula (I-A):




embedded image


or a salt, ester, amide, or prodrug thereof,


wherein


X is N or CR5′, wherein R5′ is selected from hydrogen, halogen, OR6, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloheteroalkyl, an optionally substituted C1-C6 alkenyl, and an optionally substituted C1-C6 alkynyl;


R1 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, CH2NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, an optionally substituted C1-C6 heteroalkyl, CO2R6, CONR7R8, SO3R6, and SO2NR7R8;


R2 and R3 are independently selected from hydrogen, halogen, OR6, NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, and an optionally substituted C1-C6 heteroalkyl.


Some embodiments include a compound represented by Formula (II):




embedded image


or a salt, ester, amide, or prodrug thereof.


Some embodiments include a compound represented by Formula (III):




embedded image


or a salt, ester, amide, or prodrug thereof,


wherein


X is N or CR5′, wherein R5′ is selected from hydrogen, halogen, OR6, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloheteroalkyl, an optionally substituted C1-C6 alkenyl, and an optionally substituted C1-C6 alkynyl;


R1 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, CH2NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, an optionally substituted C1-C6 heteroalkyl, CO2R6, CONR7R8, SO3R6, and SO2NR7R8;


R2 and R3 are independently selected from hydrogen, halogen, OR6, NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, and an optionally substituted C1-C6 heteroalkyl.


In some embodiments, W is S.


In some embodiments, X is N.


In some embodiments, Y is CR9.


In some embodiments, R4 is selected from the group consisting of pyridyl, pyrazolyl, cyano, triazolyl, and oxazolyl.


In some embodiments, Y is N.


In some embodiments, R4 is selected from the group consisting of pyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, and C1-C6 alkyl.


Some embodiments include a compound represented by Formula (IV):




embedded image


or a salt, ester, amide, or prodrug thereof,


wherein:


X is N or CR5′, wherein R5′ is selected from hydrogen, halogen, OR6, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloheteroalkyl, an optionally substituted C1-C6 alkenyl, and an optionally substituted C1-C6 alkynyl;


R1 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, CH2NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, an optionally substituted C1-C6 heteroalkyl, CO2R6, CONR7R8, SO3R6, and SO2NR7R8; and


R2 and R3 are independently selected from hydrogen, halogen, OR6, NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, and an optionally substituted C1-C6 heteroalkyl.


In some embodiments, X is N.


Some embodiments include a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable carrier.


Some embodiments include a method of treating a disorder responsive to inhibition of Interleukin-1 Receptor-Associated Kinase-mediated signal transduction comprising administering to a subject in need thereof an effective amount of a compound provided herein.


In some embodiments, the disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is selected from the group consisting of osteoarthritis, rheumatoid arthritis, multiple sclerosis, corneal ulcers, uveitis, and inflammatory bowel disease.


In some embodiments, the disorder is a skin disorder. In some embodiments, the skin disorder is selected from the group consisting of dermatitis, cutaneous eosinophilias, Lichen planus, urticaria, psoriasis, pruritus, angiodermas, chronic skin ulcers, conjunctivitis, vasculitides, and erythemas.


In some embodiments, the disorder is a respiratory disorder. In some embodiments, the respiratory disorder is selected from the group consisting of asthma, rhinitis, chronic obstructive pulmonary disease, bronchitis, nasal polyposis, nasal congestion, farmer's lung, fibroid lung and cough.


In some embodiments, the disorder is selected from the group consisting of diabetes, obesity, allergic disease, cancer, and sepsis.


Some embodiments include use of a compound provided herein in the preparation of a medicament for treating a disorder responsive to inhibition of Interleukin-1 Receptor-Associated Kinase-mediated signal transduction.


In some embodiments, the disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is selected from the group consisting of osteoarthritis, rheumatoid arthritis, multiple sclerosis, corneal ulcers, uveitis, and inflammatory bowel disease.


In some embodiments, the disorder is a skin disorder. In some embodiments, the skin disorder is selected from the group consisting of dermatitis, cutaneous eosinophilias, Lichen planus, urticaria, psoriasis, pruritus, angiodermas, chronic skin ulcers, conjunctivitis, vasculitides, and erythemas.


In some embodiments, the disorder is a respiratory disorder. In some embodiments, the respiratory disorder is selected from the group consisting of asthma, rhinitis, chronic obstructive pulmonary disease, bronchitis, nasal polyposis, nasal congestion, farmer's lung, fibroid lung and cough.


In some embodiments, the disorder is selected from the group consisting of diabetes, obesity, allergic disease, cancer, and sepsis.


Some embodiments include a compound provided herein for treating a disorder responsive to inhibition of Interleukin-1 Receptor-Associated Kinase-mediated signal transduction.


In some embodiments, the disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is selected from the group consisting of osteoarthritis, rheumatoid arthritis, multiple sclerosis, corneal ulcers, uveitis, and inflammatory bowel disease.


In some embodiments, the disorder is a skin disorder. In some embodiments, the skin disorder is selected from the group consisting of dermatitis, cutaneous eosinophilias, Lichen planus, urticaria, psoriasis, pruritus, angiodermas, chronic skin ulcers, conjunctivitis, vasculitides, and erythemas.


In some embodiments, the disorder is a respiratory disorder. In some embodiments, the respiratory disorder is selected from the group consisting of asthma, rhinitis, chronic obstructive pulmonary disease, bronchitis, nasal polyposis, nasal congestion, farmer's lung, fibroid lung and cough.


In some embodiments, the disorder is selected from the group consisting of diabetes, obesity, allergic disease, cancer, and sepsis.







DETAILED DESCRIPTION

Compounds and methods in the fields of chemistry and medicine are disclosed. Some of the disclosed embodiments include compounds, compositions and methods of using heterocycle amines. Some of the disclosed embodiments include heterocycle amines useful to treat inflammatory disorders.


Some embodiments include a compound of Formula (I):




embedded image


or a salt, ester, amide, or prodrug thereof,


wherein



custom character is a single or double bond;


W is selected from CH, CH—CH, O, S, NR6, and CO;


Y is N or CR9;


Z is N or C, and Z is N if W is CH and Y is CR9;


R4 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted carbocycle, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, CO2R6, SO3R6, SO2R6 and SO2NR7R8;


R5 is selected from hydrogen, halogen, OR6, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloheteroalkyl, an optionally substituted C1-C6 alkenyl, and an optionally substituted C1-C6 alkynyl;


or R4 and R5 are linked to form an optionally substituted non-aromatic ring;


each R6 is independently selected from an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted non-aromatic ring, each optionally fused with a substituted aryl or a substituted heteroaryl, hydrogen, an optionally substituted C1-C10 alkyl, an optionally substituted C1-C10 haloalkyl, and an optionally substituted C1-C10 heteroalkyl;


each R7 and R8 is independently selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, each optionally fused with a substituted aryl or a substituted heteroaryl, hydrogen, an optionally substituted C1-C10 alkyl, an optionally substituted C1-C10 haloalkyl, an optionally substituted C1-C10 alkenyl, an optionally substituted C1-C10 alkynyl, and an optionally substituted C1-C10 heteroalkyl, or R7 and R8 are linked to form an optionally substituted non-aromatic ring;


R9 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, CO2R6, SO3R6, and SO2NR7R8;


A is an optionally substituted aryl or an optionally substituted heteroaryl group;


each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, heterohaloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic ring, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, ═O, ═S, amino, and protected derivatives of amino groups.


In some embodiments, R4 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted carbocycle, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, CO2R6, SO3R6, SO2R6 and SO2NR7R8


In some embodiments, if R4 is pyrazolyl, the pyrazolyl is not substituted with aryl or heteroaryl groups.


In some embodiments, if R4 is oxazolyl, isoxazolyl, or imidazoyl, the oxazolyl, isoxazolyl, or imidazoyl radical is not substituted with aryl or heteroaryl groups.


Some embodiments include a compound represented by Formula (I-A):




embedded image


or a salt, ester, amide, or prodrug thereof,


wherein


X is N or CR5′, wherein R5′ is selected from hydrogen, halogen, OR6, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloheteroalkyl, an optionally substituted C1-C6 alkenyl, and an optionally substituted C1-C6 alkynyl;


R1 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, CH2NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, an optionally substituted C1-C6 heteroalkyl, CO2R6, CONR7R8, SO3R6, and SO2NR7R8;


R2 and R3 are independently selected from hydrogen, halogen, OR6, NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, and an optionally substituted C1-C6 heteroalkyl.


Some embodiments include a compound represented by Formula (II):




embedded image


or a salt, ester, amide, or prodrug thereof.


Some embodiments include a compound represented by Formula (III):




embedded image


or a salt, ester, amide, or prodrug thereof,


wherein


X is N or CR5′, wherein R5′ is selected from hydrogen, halogen, OR6, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloheteroalkyl, an optionally substituted C1-C6 alkenyl, and an optionally substituted C1-C6 alkynyl;


R1 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, CH2NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, an optionally substituted C1-C6 heteroalkyl, CO2R6, CONR7R8, SO3R6, and SO2NR7R8;


R2 and R3 are independently selected from hydrogen, halogen, OR6, NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, and an optionally substituted C1-C6 heteroalkyl.


In some embodiments, W is S.


In some embodiments, X is N.


In some embodiments, Y is CR9.


In some embodiments, R4 is selected from the group consisting of pyridyl, pyrazolyl, cyano, triazolyl, and oxazolyl.


In some embodiments, Y is N.


In some embodiments, R4 is selected from the group consisting of pyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, and C1-C6 alkyl.


Some embodiments include a compound represented by Formula (IV):




embedded image


or a salt, ester, amide, or prodrug thereof,


wherein:


X is N or CR5′, wherein R5′ is selected from hydrogen, halogen, OR6, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloheteroalkyl, an optionally substituted C1-C6 alkenyl, and an optionally substituted C1-C6 alkynyl;


R1 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, CH2NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, an optionally substituted C1-C6 heteroalkyl, CO2R6, CONR7R8, SO3R6, and SO2NR7R8; and


R2 and R3 are independently selected from hydrogen, halogen, OR6, NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, and an optionally substituted C1-C6 heteroalkyl.


In some embodiments, X is N.


DEFINITIONS

Unless specific definitions are provided, the nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms “hydrogen” and “H” are understood to have identical meaning. Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques may be performed e.g., using kits according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein by reference in its entirety for any purpose.


The term “alkyl” refers to a branched or unbranched aliphatic hydrocarbon group. An alkyl may be a “saturated alkyl,” which means that it does not contain any alkene or alkyne groups. An alkyl group may be an “unsaturated alkyl,” which means that it comprises at least one alkene or alkyne group. An alkyl, whether saturated or unsaturated, may be branched or straight chain. Alkyls may be cyclic or non-cyclic. Cyclic alkyls may include multicyclic systems including fused alkyl rings. Alkyls may be substituted or unsubstituted. Alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, each of which may be optionally substituted.


In certain embodiments, an alkyl comprises 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term “alkyl” also includes instances where no numerical range of carbon atoms is designated).


The term “lower alkyl” refers to an alkyl comprising 1 to 5 carbon atoms. The term “medium alkyl” refers to an alkyl comprising 5 to 10 carbon atoms. An alkyl may be designated as “C1-C4 alkyl” or similar designations. By way of example only, “C1-C4 alkyl” indicates an alkyl having one, two, three, or four carbon atoms, e.g., the alkyl is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.


The term “alkenyl” refers to an alkyl group comprising at least one carbon-carbon double bond, including by way of non-limiting example ethenyl, propenyl, and butenyl.


The term “alkynyl” refers to an alkyl group comprising at least one carbon-carbon triple bond, including by way of non-limiting example ethynyl, propynyl, and butynyl.


The term “haloalkyl” refers to an alkyl in which at least one hydrogen atom is replaced with a halogen atom. In certain of the embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another. In certain of such embodiments, the halogen atoms are not all the same as one another.


The term “heteroalkyl” refers to a branched or unbranched aliphatic hydrocarbon group comprising one or more oxygen, sulfur, nitrogen, or NH. Examples of heteroalkyls include, but are not limited to, CH3C(═O)CH2—, CH3C(═O)CH2CH2—, CH3CH2C(═O)CH2CH2—, CH3C(═O)CH2CH2CH2—, CH3NHC(═O)CH2—, CH3C(═O)NHCH2—, CH3OCH2CH2—, CH3NHCH2—, and the like.


The term “straight-chain alkoxy” refers to a group comprising the formula: (CH2)pO— wherein p is any integer. Straight-chain alkoxy does not include substituted or branched alkoxy groups.


The term “non-straight-chain-alkoxy-heteroalkyl” refers to any heteroalkyl that is not a straight-chain alkoxy heteroalkyl. Thus, for example, non-straight-chain-alkoxy heteroalkyls include, but are not limited to: 2,2-isopropyloxy; 1,2-propyloxy; 1,1-ethyloxy; methylamino; ethylamino; propylamino; methylpyrrolidino; and methylpiperidino.


The term “heterohaloalkyl” refers to a heteroalkyl in which at least one hydrogen atom is replaced with a halogen atom.


The term “carbocycle” refers to a group comprising a covalently closed ring, wherein each of the atoms that forms and/or comprises the ring is a carbon atom. Carbocylic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycles may be optionally substituted.


The term “heterocycle” refers to a group comprising a covalently closed ring wherein at least one atom that forms and/or comprises the ring is a heteroatom. Heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Any number of those atoms may be heteroatoms (i.e., a heterocyclic ring may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms). In heterocyclic rings comprising two or more heteroatoms, those two or more heteroatoms may be the same or different from one another. Heterocycles may be optionally substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom. For example, binding for benzo-fused derivatives, may be via a carbon of the benzenoid ring. Examples of heterocycles include, but are not limited to the following:




embedded image


wherein D, E, F, and G independently represent a heteroatom. Each of D, E, F, and G may be the same or different from one another.


The term “heteroatom” refers to an atom other than carbon or hydrogen. Heteroatoms, typically, are independently selected from oxygen, sulfur, nitrogen, and phosphorus, but heteroatoms are not limited to those atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may all be the same as one another, or some or all of the two or more heteroatoms may each be different from the others.


The term “aromatic” refers to a group comprising a covalently closed ring having a delocalized π-electron system. Aromatic rings may be formed by five, six, seven, eight, nine, or more than nine atoms. Aromatics may be optionally substituted. Examples of aromatic groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl. The term aromatic includes, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from an aryl, a heteroaryl, a cycloalkyl, a non-aromatic ring, a halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a C1-6 alkoxy, a C1-6 alkyl, a C1-6 hydroxyalkyl, a C1-6 aminoalkyl, a C1-6 alkylamino, an alkylsulfenyl, an alkylsulfinyl, an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl. In certain embodiments, an aromatic group is substituted at one or more of the para, meta, and/or ortho positions. Examples of aromatic groups comprising substitutions include, but are not limited to, phenyl, 3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4-morpholin-4-ylphenyl, 4-pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin-1-yl)phenyl.


The term “aryl” refers to an aromatic group wherein each of the atoms forming the ring is a carbon atom. Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups may be optionally substituted.


The term “heteroaryl” refers to an aromatic group wherein at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-8 heterocyclic groups comprising one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms. In certain embodiments, heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C1-6-alkoxy, C1-6-hydroxyalkyl, C1-6-aminoalkyl, C1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine, pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, C1-6-alkyl, hydroxy-C1-6-alkyl, and amino-C1-6-alkyl.


The term “non-aromatic ring” refers to a group comprising a covalently closed ring that does not have a delocalized π-electron system in its principle and/or predominant tautomer.


The term “cycloalkyl” refers to a group comprising a non-aromatic ring wherein each of the atoms forming the ring is a carbon atom. Cycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Cycloalkyls may include multicyclic systems (e.g., fused ring systems). Cycloalkyls may be optionally substituted.


In certain embodiments, a cycloalkyl comprises one or more unsaturated bonds. Examples of cycloalkyls include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, and cycloheptene.


The term “non-aromatic ring” refers to a group comprising a non-aromatic ring moiety wherein the atoms that form and/or comprise the ring include carbon and/or heteroatoms. When heteroatoms are included in the ring, one or more such heteroatoms may be present. Non-aromatic rings also optionally include one or more carbonyl or thiocarbonyl groups as part of the ring. Non-aromatic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Non-aromatic rings may be optionally substituted. Examples of non-aromatic rings include, but are not limited to, cycloalkyls (including but not limited to cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, and cycloheptene), lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane.


The term “arylalkyl” refers to a group comprising an aryl group bound to an alkyl group.


The term “ring” refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocyclic rings), aromatics (e.g., aryls and heteroaryls), and non-aromatic rings. Rings may be optionally substituted. Rings may form part of a ring system.


The term “ring system” refers to a either a single ring or two or more rings, wherein, if two or more rings are present, the two or more of the rings are fused. The term “fused” refers to structures in which two or more rings share one or more bonds.


The substituent “R” appearing by itself and without a number designation refers to a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic ring (bonded through a ring carbon).


The term “O-carboxy” refers to the group consisting of formula RC(═O)O—.


The term “C-carboxy” refers to the group consisting of formula —C(═O)OR.


The term “acetyl” refers to the group consisting of formula —C(═O)CH3.


The term “trihalomethanesulfonyl” refers to the group consisting of formula X3CS(═O)2— where X is a halogen.


The term “cyano” refers to the group consisting of formula —CN.


The term “isocyanato” refers to the group consisting of formula —NCO.


The term “thiocyanato” refers to the group consisting of formula —CNS.


The term “isothiocyanato” refers to the group consisting of formula —NCS.


The term “sulfonyl” refers to the group consisting of formula —S(═O)—R.


The term “S-sulfonamido” refers to the group consisting of formula —S(═O)2NR.


The term “N-sulfonamido” refers to the group consisting of formula RS(═O)2NH—.


The term “trihalomethanesulfonamido” refers to the group consisting of formula X3CS(═O)2NR—.


The term “O-carbamyl” refers to the group consisting of formula —OC(═O)—NR.


The term “N-carbamyl” refers to the group consisting of formula ROC(═O)NH—.


The term “O-thiocarbamyl” refers to the group consisting of formula —OC(═S)—NR.


The term “N-thiocarbamyl” refers to the group consisting of formula ROC(═S)NH—.


The term “C-amido” refers to the group consisting of formula —C(═O)—NR2.


The term “N-amido” refers to the group consisting of formula RC(═O)NH—.


The term “oxo” refers to the group consisting of formula ═O.


The term “carbonyl” refers to the group consisting of formula C(═O)R.


The term “thiocarbonyl” refers to the group consisting of formula C(═S)R.


The term “dihydropyrazolylene” refers to a di-radical of an optionally substituted dihydropyrazole ring, wherein the dihydropyrazole ring has the structure:




embedded image



and wherein the two radicals may be at any positions on the ring.


The term “pyrazolyl” refers to a radical of a pyrazole ring, wherein the pyrazole ring has the structure:




embedded image



and wherein the radical may be at any position on the ring.


The term “ester” refers to a chemical moiety with formula —(R)n—COOR′, where R and R′ are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic ring (bonded through a ring carbon), where n is 0 or 1.


The term “amide” refers to a chemical moiety with formula —(R)n—C(O)NHR′ or —(R)n—NHC(O)R′, where R and R′ are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is 0 or 1. In certain embodiments, an amide may be an amino acid or form part of a peptide.


The terms “amine,” “hydroxy,” and “carboxyl” include such groups that have been esterified or amidified. Procedures and specific groups used to achieve esterification and amidification are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein in its entirety.


Unless otherwise indicated, the term “optionally substituted” refers to a group in which none, one, or more than one of the hydrogen atoms has been replaced with one or more group(s) individually and independently selected from: alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic ring, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, oxo, and amino, including mono- and di-substituted amino groups, and the protected derivatives of amino groups. Such protective derivatives (and protecting groups that may form such protective derivatives) are known to those of skill in the art and may be found in references such as Greene and Wuts, above. In embodiments in which two or more hydrogen atoms have been substituted, the substituent groups may together form a ring.


Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.


The term “carrier” refers to a compound that facilitates the incorporation of another compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier for improving incorporation of certain organic compounds into cells or tissues.


The term “pharmaceutical agent” refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a patient. In certain embodiments, a pharmaceutical agent comprises an active agent, which is the agent that induces the desired therapeutic effect. In certain embodiments, a pharmaceutical agent comprises a prodrug. In certain embodiments, a pharmaceutical agent comprises inactive ingredients such as carriers, excipients, and the like.


The term “therapeutically effective amount” refers to an amount of a pharmaceutical agent sufficient to achieve a desired therapeutic effect.


The term “prodrug” refers to a pharmaceutical agent that is converted from a less active form into a corresponding more active form in vivo.


The term “pharmaceutically acceptable” refers to a formulation of a compound that does not significantly abrogate the biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient.


The term “co-administer” refers to administering more than one pharmaceutical agent to a patient. In certain embodiments, co-administered pharmaceutical agents are administered together in a single dosage unit. In certain embodiments, co-administered pharmaceutical agents are administered separately. In certain embodiments, co-administered pharmaceutical agents are administered at the same time. In certain embodiments, co-administered pharmaceutical agents are administered at different times.


The term “patient” includes human and animal subjects.


The term “substantially pure” means an object species (e.g., compound) is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition). In certain embodiments, a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all species present. In certain embodiments, a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all species present in the composition. In certain embodiments, the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single species.


Certain Compounds


In certain embodiments, compounds of Formula (I) are provided:




embedded image


or a salt, ester, amide, or prodrug thereof,


wherein custom character is a single or double bond;


W is selected from CH, CH—CH, O, S, NR6, and CO;


Y is N or CR9;


Z is N or C, and Z is N if W is CH and Y is CR9;


R4 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted carbocycle, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, CO2R6, SO3R6, SO2R6 and SO2NR7R8;


R5 is selected from hydrogen, halogen, OR6, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloheteroalkyl, an optionally substituted C1-C6 alkenyl, and an optionally substituted C1-C6 alkynyl;


or R4 and R5 are linked to form an optionally substituted non-aromatic ring;


each R6 is independently selected from an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted non-aromatic ring, each optionally fused with a substituted aryl or a substituted heteroaryl, hydrogen, an optionally substituted C1-C10 alkyl, an optionally substituted C1-C10 haloalkyl, and an optionally substituted C1-C10 heteroalkyl;


each R7 and R8 is independently selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, each optionally fused with a substituted aryl or a substituted heteroaryl, hydrogen, an optionally substituted C1-C10 alkyl, an optionally substituted C1-C10 haloalkyl, an optionally substituted C1-C10 alkenyl, an optionally substituted C1-C10 alkynyl, and an optionally substituted C1-C10 heteroalkyl, or R7 and R8 are linked to form an optionally substituted non-aromatic ring;


R9 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, CO2R6, SO3R6, and SO2NR7R8;


A is an optionally substituted aryl or an optionally substituted heteroaryl group;


each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, heterohaloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic ring, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, ═O, ═S, amino, and protected derivatives of amino groups.


In some embodiments, R4 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted carbocycle, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, CO2R6, SO3R6, SO2R6 and SO2NR7R8


In some embodiments, if R4 is pyrazolyl, the pyrazolyl is not substituted with aryl or heteroaryl groups.


In some embodiments, if R4 is oxazolyl, isoxazolyl, or imidazoyl, the oxazolyl, isoxazolyl, or imidazoyl radical is not substituted with aryl or heteroaryl groups.


Some embodiments include a compound represented by Formula (I-A):




embedded image


or a salt, ester, amide, or prodrug thereof,


wherein


X is N or CR5′, wherein R5′ is selected from hydrogen, halogen, OR6, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloheteroalkyl, an optionally substituted C1-C6 alkenyl, and an optionally substituted C1-C6 alkynyl;


R1 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, CH2NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, an optionally substituted C1-C6 heteroalkyl, CO2R6, CONR7R8, SO3R6, and SO2NR7R8;


R2 and R3 are independently selected from hydrogen, halogen, OR6, NR7R8, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, and an optionally substituted C1-C6 heteroalkyl.


Some embodiments include a compound represented by Formula (II), (III), or (IV):




embedded image


or a salt, ester, amide, or prodrug thereof,


wherein:


W is selected from O, S, NR6, and CO;


X is N or CR5;


Y is N or CR9;


R4 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted carbocycle, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, CO2R6, SO3R6, and SO2NR7R8;


each R5 is independently selected from hydrogen, halogen, OR6, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 haloheteroalkyl, an optionally substituted C1-C6 alkenyl, and an optionally substituted C1-C6 alkynyl;


or R4 and R5 are linked to form an optionally substituted non-aromatic ring;


each R6 is independently selected from hydrogen, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted C1-C10 alkyl, an optionally substituted C1-C10 haloalkyl, and an optionally substituted C1-C10 heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl;


each R7 and R8 is independently selected from hydrogen, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted C1-C10 alkyl, an optionally substituted C1-C10 haloalkyl, an optionally substituted C1-C10 alkenyl, an optionally substituted C1-C10 alkynyl, and an optionally substituted C1-C10 heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R7 and R8 are linked to form an optionally substituted non-aromatic ring;


R9 is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, CO2R6, SO3R6, and SO2NR7R8;


A is an optionally substituted aryl or an optionally substituted heteroaryl group;


each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, heterohaloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic ring, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, ═O, ═S, amino, and protected derivatives of amino groups.


In some embodiments, if R4 is a pyrazolyl, oxazolyl, isoxazolyl, or imidazoyl radical in compounds of Formula (II), (III), or (IV), the pyrazolyl, oxazolyl, isoxazolyl, or imidazoyl radical is not substituted with aryl or heteroaryl groups.


In some specific embodiments, if R4 is a pyrazolyl radical in compounds of Formula (II), (III), or (IV), the pyrazolyl is not substituted with aryl or heteroaryl groups.


Certain Synthetic Methods


In certain embodiments, compounds of the present invention can by synthesized using the following Schemes.




embedded image


Scheme I describes the synthesis of aminopyridine substituted benzothiazoles. An aminopyridine 1 is treated with a base such as NaH and reacted with 6-bromo-2-chlorobenzothiazole 2 to afford compounds of structure 3. Palladium catalyzed coupling of structure 3 with a boronic acid affords compounds of structure 4.




embedded image


Scheme II describes the synthesis of aminopyridine substituted benzothiazoles. Aminopyridine 1 is converted to an isothiocyanate 5 and reacted with an aniline 6, to give a thiourea 7. The thiourea is oxidatively cyclized with, for example, bromine to give the benzothiazole 4.




embedded image


Scheme III describes the synthesis of aminopyridine substituted imidazopyridines 10. A 2-halopyridine, such as compound 8, is coupled with an aminoimidazopyridine, such as 9, under the influence of a palladium catalyst and a base to furnish products 10.


One of skill in the art will recognize that analogous synthetic schemes may be used to synthesize similar compounds. One of skill will recognize that compounds of the present invention may be synthesized using other synthesis schemes. In certain embodiments, the invention provides a salt corresponding to any of the compounds provided herein.


Certain Pharmaceutical Agents


Some embodiments include pharmaceutical agents. In some embodiments a pharmaceutical agent can include a compound and/or composition provided herein and a pharmaceutical carrier. In certain embodiments, at least one compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt, ester, amide, and/or prodrug thereof, either alone or combined with one or more pharmaceutically acceptable carriers, forms a pharmaceutical agent. Techniques for formulation and administration of compounds of the present embodiments may be found for example, in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., 18th edition, 1990, which is incorporated herein by reference in its entirety.


In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.


In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is a liquid (e.g., a suspension, elixir and/or solution). In certain of such embodiments, a liquid pharmaceutical agent comprising one or more compounds of the present embodiments is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.


In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is a solid (e.g., a powder, tablet, and/or capsule). In certain of such embodiments, a solid pharmaceutical agent comprising one or more compounds of the present embodiments is prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.


In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.


In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments comprises a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical agents including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.


In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments comprises one or more tissue-specific delivery molecules designed to deliver the pharmaceutical agent to specific tissues or cell types. For example, in certain embodiments, pharmaceutical agents include liposomes coated with a tissue-specific antibody.


In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments comprises a co-solvent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.


In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments comprises a sustained-release system. A non-limiting example of such a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers. In certain embodiments, sustained-release systems may, depending on their chemical nature, release compounds over a period of hours, days, weeks or months.


Certain compounds used in pharmaceutical agent of the present embodiments may be provided as pharmaceutically acceptable salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.


In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments comprises an active ingredient in a therapeutically effective amount. In certain embodiments, the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.


In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is formulated as a prodrug. In certain embodiments, prodrugs are useful because they are easier to administer than the corresponding active form. For example, in certain instances, a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form. In certain instances, a prodrug may have improved solubility compared to the corresponding active form. In certain embodiments, a prodrug is an ester. In certain embodiments, such prodrugs are less water soluble than the corresponding active form. In certain instances, such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility. In certain embodiments, the ester in such prodrugs is metabolically hydrolyzed to carboxylic acid. In certain instances the carboxylic acid containing compound is the corresponding active form. In certain embodiments, a prodrug comprises a short peptide (polyaminoacid) bound to an acid group. In certain of such embodiments, the peptide is metabolized to form the corresponding active form.


In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is useful for treating a condition or disorder in a mammal, such as a human. Suitable administration routes include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous). In certain embodiments, pharmaceutical intrathecals are administered to achieve local rather than systemic exposures. For example, pharmaceutical agents may be injected directly in the area of desired effect (e.g., in the renal or cardiac area).


In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present embodiments is administered in the form of a dosage unit (e.g., tablet, capsule, bolus, etc.). In certain embodiments, such dosage units comprise a compound or composition provided herein, such as a compound or composition comprising Formula (I), (II), (III), or (IV), in a dose from about 1 μg/kg of body weight to about 50 mg/kg of body weight, and from about 2 μg/kg of body weight to about 25 mg/kg of body weight, from about 10 μg/kg of body weight to about 5 mg/kg of body weight. In certain embodiments, pharmaceutical agents are administered as needed, once per day, twice per day, three times per day, or four or more times per day. It is recognized by those skilled in the art that the particular dose, frequency, and duration of administration depends on a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the pharmaceutical agent.


In certain embodiments, a pharmaceutical agent comprising a compound of the present embodiments is prepared for oral administration. In certain of such embodiments, a pharmaceutical agent is formulated by combining one or more compounds of the present embodiments with one or more pharmaceutically acceptable carriers. Certain of such carriers enable compounds of the present embodiments to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient. In certain embodiments, pharmaceutical agents for oral use are obtained by mixing one or more compounds of the present embodiments and one or more solid excipient. Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). In certain embodiments, such a mixture is optionally ground and auxiliaries are optionally added. In certain embodiments, pharmaceutical agents are formed to obtain tablets or dragee cores. In certain embodiments, disintegrating agents (e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate) are added.


In certain embodiments, dragee cores are provided with coatings. In certain of such embodiments, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to tablets or dragee coatings.


In certain embodiments, pharmaceutical agents for oral administration are push-fit capsules made of gelatin. Certain of such push-fit capsules comprise one or more compounds of the present embodiments in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In certain embodiments, pharmaceutical agents for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft capsules, one or more compounds of the present embodiments are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.


In certain embodiments, pharmaceutical agents are prepared for buccal administration. Certain of such pharmaceutical agents are tablets or lozenges formulated in conventional manner.


In certain embodiments, a pharmaceutical agent is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In certain of such embodiments, a pharmaceutical agent comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical agents for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical agents for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical agents for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.


In certain embodiments, a pharmaceutical agent is prepared for transmucosal administration. In certain of such embodiments penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.


In certain embodiments, a pharmaceutical agent is prepared for administration by inhalation. Certain of such pharmaceutical agents for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer. Certain of such pharmaceutical agents comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In certain embodiments using a pressurized aerosol, the dosage unit may be determined with a valve that delivers a metered amount. In certain embodiments, capsules and cartridges for use in an inhaler or insufflator may be formulated. Certain of such formulations comprise a powder mixture of a compound of the present embodiments and a suitable powder base such as lactose or starch.


In certain embodiments, a pharmaceutical agent is prepared for rectal administration, such as a suppositories or retention enema. Certain of such pharmaceutical agents comprise known ingredients, such as cocoa butter and/or other glycerides.


In certain embodiments, a pharmaceutical agent is prepared for topical administration. Certain of such pharmaceutical agents comprise bland moisturizing bases, such as ointments or creams. Exemplary suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, lanolin and water in oil emulsions such as Eucerin™, available from Beiersdorf (Cincinnati, Ohio). Exemplary suitable cream bases include, but are not limited to, Nivea™ Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose Cream™, available from Johnson & Johnson (New Brunswick, N.J.), hydrophilic ointment (USP) and Lubriderm™, available from Pfizer (Morris Plains, N.J.).


In certain embodiments, the formulation, route of administration and dosage for a pharmaceutical agent of the present embodiments can be chosen in view of a particular patient's condition. In certain embodiments, a pharmaceutical agent is administered as a single dose. In certain embodiments, a pharmaceutical agent is administered as a series of two or more doses administered over one or more days.


In certain embodiments, a pharmaceutical agent of the present embodiments is administered to a patient between about 0.1% and 500%, 5% and 200%, 10% and 100%, 15% and 85%, 25% and 75%, or 40% and 60% of an established human dosage. Where no human dosage is established, a suitable human dosage may be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies.


In certain embodiments, a daily dosage regimen for a patient comprises an oral dose of between 0.1 mg and 2000 mg, 5 mg and 1500 mg, 10 mg and 1000 mg, 20 mg and 500 mg, 30 mg and 200 mg, or 40 mg and 100 mg of a compound of the present embodiments. In certain embodiments, a daily dosage regimen is administered as a single daily dose. In certain embodiments, a daily dosage regimen is administered as two, three, four, or more than four doses.


In certain embodiments, a pharmaceutical agent of the present embodiments is administered by continuous intravenous infusion. In certain of such embodiments, from 0.1 mg to 500 mg of a composition of the present embodiments is administered per day.


In certain embodiments, a pharmaceutical agent of the present embodiments is administered for a period of continuous therapy. For example, a pharmaceutical agent of the present embodiments may be administered over a period of days, weeks, months, or years.


Dosage amount, interval between doses, and duration of treatment may be adjusted to achieve a desired effect. In certain embodiments, dosage amount and interval between doses are adjusted to maintain a desired concentration of compound in a patient. For example, in certain embodiments, dosage amount and interval between doses are adjusted to provide plasma concentration of a compound of the present embodiments at an amount sufficient to achieve a desired effect. In certain of such embodiments the plasma concentration is maintained above the minimal effective concentration (MEC). In certain embodiments, pharmaceutical agents of the present embodiments are administered with a dosage regimen designed to maintain a concentration above the MEC for 10-90% of the time, between 30-90% of the time, or between 50-90% of the time.


In certain embodiments in which a pharmaceutical agent is administered locally, the dosage regimen is adjusted to achieve a desired local concentration of a compound of the present embodiments.


In certain embodiments, a pharmaceutical agent may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound of the present embodiments formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.


In certain embodiments, a pharmaceutical agent is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.


Certain Therapeutic Methods


Some compounds and compositions provided herein, such as compounds and/or compositions comprising Formula (I), (II), (III), and (IV) are useful for the treatment of a variety of diseases and disorders. Examples of diseases and disorders include inflammatory disorders, cell proliferative disorders, and immune-related disorders, and disorders associated with IRAK-mediated signal transduction.


Inflammation of tissues and organs occurs in a wide range of disorders and diseases and in certain variations results from activation of the cytokine family of receptors. Example inflammatory disorders associated with activation of IRAK kinases and/or disorders IRAK-mediated signal transduction include skin disorders, respiratory disorders, and other disorders with an allergic component. These disorders are treated or prevented by modulation of IRAK activity, for example, by administration of certain compounds and/or compositions provided herein. In some embodiments, methods of treating a subject in need thereof include administering an effective amount of a compound or composition provided herein. Some embodiments include treating a disorder responsive to inhibition of IRAK-mediated signal transduction.


Example skin disorders include dermatitis, cutaneous eosinophilias, Lichen planus, urticaria, psoriasis, pruritus, angiodermas, chronic skin ulcers, conjunctivitis, vasculitides, or erythemas. Examples of respiratory disorders include asthma, rhinitis, chronic obstructive pulmonary disease, bronchitis, nasal polyposis, nasal congestion, farmer's lung, fibroid lung and cough. Other example diseases that may be treated with the compounds and compositions provided herein include osteoarthritis, rheumatoid arthritis, multiple sclerosis, corneal ulcers, uveitis, pain and inflammatory bowel disease. More example disorders include diabetes, obesity, allergic disease, cancer, and sepsis.


In some embodiments, the compounds and compositions provided herein can be administered in combination with an additional active agent. Examples of other active agents include anti-inflammatory agents, analgesic agents, such as: opiate agonists; lipoxygenase inhibitors; cyclooxygenase inhibitors, such as cyclooxygenase-2 inhibitors; interleukin inhibitors, such as interleukin-1 receptor antagonist; NMDA antagonists; inhibitors of nitric oxide or inhibitors of the synthesis of nitric oxide; a non-steroidal anti-inflammatory agent; or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sulindac, tenidap, and the like. In some embodiments, the instant compounds and/or compositions may be administered with: a potentiator such as caffeine, an H2-antagonist (e.g., ranitidine), simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextromethorphan; a diuretic; and a sedating or non-sedating antihistamine.


More examples of additional active agents include (a) VLA-4 antagonists; (b) corticosteroids, such as beclomethasone, methylprednisolone, betamethasone, prednisone, prednisolone, dexamethasone, fluticasone and hydrocortisone, and corticosteroid analogs such as budesonide; (c) immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirclimus, Rapamune®) and other FK-506 type immunosuppressants, and mycophenolate, e.g., mycophenolate mofetil (CellCept®); (d) antihistamines (H1-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidal anti-asthmatics such as β2-agonists (e.g., terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (e.g., zafirlukast, montelukast, pranlukast, iralukast, pobilukast and SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac), fenamic acid derivatives (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivative (e.g., diflunisal and flufenisal), oxicams (e.g., isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (e.g., acetyl salicylic acid, sulfasalazine and analogs, mesalamine) and the pyrazolones (e.g., apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (h) inhibitors of phosphodiesterase type IV (PDE-IV); (i) interleukin inhibitors, such as interleukin-1 (IL-1) inhibitors, and chemokine receptor antagonists; j) cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and other statins), bile acid sequestrants (e.g., cholestyramine and colestipol), nicotinic acid (niacin), fibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), probucol and nitroglycerin; (k) anti-diabetic agents such as insulin, sulfonylureas (e.g., glyburide, meglinatide), biguanides, e.g., metformin (Glucophage®), α-glucosidase inhibitors (acarbose), thiazolidinone compounds, e.g., rosiglitazone (Avandia®), troglitazone (Rezulin®) and pioglitazone (Actos®); (l) preparations of interferon beta (interferon β-1α, interferon β-1β; (m) gold compounds such as auranofin and aurothioglucose, (n) etanercept (Enbrel®), (o) antibody therapies such as orthoclone (OKT3), daclizumab (Zenapax®), basiliximab (Simulect®), infliximab (Remicade®) and D2E6 TNF antibody, (p) lubricants or emollients such as petrolatum and lanolin, (q) keratolytic agents, (r) vitamin D3 derivatives, e.g., calcipotriene or calcipotriol (Dovonex®), (s) PUVA, (t) anthralin (Drithrocreme®), (u) etretinate (Tegison®) and isotretinoin, (v) multiple sclerosis therapeutic agents such as β-1β (Betaseron®), interferon β-1α(Avonex®), azathioprine (Imurek®, Imuran®), glatiramer acetate (Capoxone®), a glucocorticoid (e.g., prednisolone) and cyclophosphamide and (w) β3 adrenergic receptor agonists, leptin or derivatives thereof, and neuropeptide Y (e.g., NPY5) antagonists; (x) other compounds such as 5-aminosalicylic acid and prodrugs thereof; (y) DNA-alkylating agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g., azathioprene, 6-mercaptopurine, methotrexate, a folate antagonist, and 5-fluorouracil, a pyrimidine antagonist), microtubule disruptors (e.g., vincristine, vinblastine, paclitaxel, colchicine, nocodazole and vinorelbine), DNA intercalators (e.g., doxorubicin, daunomycin and cisplatin), DNA synthesis inhibitors such as hydroxyurea, DNA cross-linking agents, e.g., mitomycin C, and hormone therapy (e.g., tamoxifen, and flutamide).


In still other particular embodiments, compounds and compositions provided herein are administered for the treatment of rheumatoid arthritis, wherein the compounds are administered either alone or in combination with a second therapeutic agent selected from methotrexate, sulfasalazine, a COX-2 inhibitor, hydroxychloroquine, cyclosporine A, D-penicillamine, infliximab, etanercept, auranofin and aurothioglucose.


In yet other particular embodiments, the present compounds are administered for the treatment of inflammatory bowel disease wherein the compound of the invention is used alone or in combination with a second therapeutic agent selected from sulfasalazine and analogs (e.g., olsalazine) mesalamine, corticosteroids (e.g., prednisone, prednisolone) and analogs (e.g., budesonide), azathioprine, 6-mercaptopurine, cyclosporine A, methotrextate, infliximab, or an IL-1 inhibitor.


In other particular embodiments, the present methods are directed to the treatment of multiple sclerosis using a compound of the invention either alone or in combination with a second therapeutic agent selected from interferon β-1β, interferon β-1α, azathioprine, glatiramer acetate, a glucocorticoid (e.g., prednisolone), and cyclophosphamide.


EXAMPLES

The following examples, including experiments and results achieved, are provided for illustrative purposes only and are not to be construed as limiting the present invention. Where chemical structures depict atoms having an unfilled valency, it is to be understood that the valency is satisfied with one or more hydrogen atoms.


Example 1
Synthesis of N-(4-hydroxymethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine (Compound 101, Structure 4 in Scheme I, R1═CH2OH, R4=4-pyridyl)



embedded image


To a solution of 4-(((tert-butyldimethylsilypoxy)methyl)pyridin-2-amine (1.92 g, 8.0 mmol, 1 eq.) in anhydrous tetrahydrofuran (THF) (100 mL) was added NaH (2.25 g, 56.0 mmol, 7.0 eq) at 0° C., after stirring at room temperature for 30 min, a solution of 6-bromo-2-chlorobenzo[d]thiazole (2.0 g, 8.1 mmol, 1 eq) in THF (20 mL) was added dropwise. Then the reaction mixture was heated to 65° C. for 2 hours. After cooling, water was added, the organic layer was separated and the aqueous was extracted with EtOAc, dried and concentrated to give 6-bromo-N-(4-(((tert-butyldimethylsilypoxy)methyl)pyridin-2-yl)benzo[d]thiazol-2-amine (1.5 g, 37%) which was used directly without further purification. 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J=9.0, 1H); 6.87 (d, J=2.6, 1H); 6.64 (dd, J=9.0, 2.6, 1H); 4.58 (t, J=5.2, 1H); 3.67 (s, 3H); 3.21 (td, J=7.1, 5.2, 2H); 2.31 (t, J=7.5, 2H); 1.70-1.59 (m, 4H); 1.46-1.29 (m, 10H).




embedded image


To a 10 mL microwave tube was added 6-bromo-N-(4-(((tert-butyldimethylsilypoxy)methyl)pyridin-2-yl)benzo[d]thiazol-2-amine (400 mg, 1.03 mmol), pyridine-4-boronic acid (185 mg, 1.5 eq), K2CO3 (425 mg, 3.09 mmol, 3 eq), Pd(dppf)Cl2, (25 mg, 0.03 mmol, 0.03 eq), LiCl (130 mg, 3.09 mmol, 3 eq) and 3 mL of dioxane/H2O (4:1). The mixture was stirred at 140° C. under microwave condition for 1 h. After cooling to room temperature (rt), the mixture was concentrated in vacuo and the residue was purified by flash chromatography to give 125 mg of N-(4-(((tert-butyldimethylsilypoxy)methyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine.




embedded image


N-(4-((Tert-butyldimethylsilypoxy)methyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine (1.8 g, 3.34 mmol, 1 eq.) was dissolved in 6 N HCl/MeOH (30 mL), and the suspension was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated and the residue was purified by chromatography to give 1.2 g of N-(4-(hydroxymethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine 101. 1HNMR (DMSO-d6, 400 MHz) δ 8.95 (d, 2H), 8.75 (s, 1H), 8.45 (d, 2H), 8.35 (d, 1H), 8.11 (d, 1H), 7.84 (d, 1H), 7.22 (s, 1H), 7.00 (d, 1H), 4.60 (s, 2H). MS (ES-API): MH+=335.0. HPLC tR=2.20 min.


Example 2
Synthesis of 6-(pyridin-4-yl)-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine (Compound 102, Structure 4 in Scheme I, R1═CH2-pyrrolidin-1-yl R4=4-pyridyl)



embedded image


(2-((6-(Pyridin-4-yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)methanol 101 (0.12 g, 0.36 mmol, 1 eq.) was dissolved in POCl3 (3 mL) under N2, and the suspension was stirred at 110° C. for 2 hours. After cooling, POCl3 was evaporated under reduced pressure and the residue was basified with sat. Na2CO3 solution, then extracted with DCM, dried and concentrated in vacuo to afford N-(4-(chloromethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine (80 mg, 63%) which was used directly in the next step.




embedded image


A solution of N-(4-(chloromethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine (80 mg, 0.23 mmol, 1 eq.) in 1 mL dioxane was treated with 15 mg of pyrrolidine and 20 mg DIEA. The reaction mixture was stirred at 140° C. under microwave condition for 1 h. After cooling to rt, the mixture was concentrated in vacuo. The residue was washed with EtOH to afford 6-(pyridin-4-yl)-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 102 without further purification (67 mg). 1HNMR (CD3OD, 400 MHz) δ 8.83 (d, 2H), 8.60 (m, 1H), 8.54 (m, 1H), 8.46 (m, 2H), 8.10 (m, 1H), 7.92 (d, 1H), 7.52 (s, 1H), 3.37 (d, 1H), 4.53 (s, 2H), 3.62 (br s, 2H), 3.25 (m, 2H overlapping with signal from CD3OD), 2.22 (m, 2H), 2.09 (m, 2H). MS (ES-API): MH+=388.1. HPLC tR=2.16 min.


Examples 3-332

Compounds 103-439 were prepared in a similar fashion as described in Examples 1-2 and their structures, names, and found molecular mass ion numbers are summarized in Table 1 (Example: E.g.; Compound: Cmpd).













TABLE 1





E.g.
Structure
Cmpd
Name
[M + H]+



















3


embedded image


103
6-(1H-pyrazol-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
377.1





4


embedded image


104
N-(4-(piperazin-1- ylmethyl)pyridin-2-yl)-6-(pyridin- 4-yl)benzo[d]thiazol-2-amine
403.1





5


embedded image


105
1-(4-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)piperazin-1- yl)ethanone
445.1





6


embedded image


106
1-(4-methylpiperazin-1-yl)-2-(2- ((6-(pyridin-4-yl)benzo[d]thiazol- 2-yl)amino)pyridin-4- yl)ethanone
445.1





7


embedded image


107
6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(pyrrolidin-1-ylmethyl)pyridin- 2-yl)benzo[d]thiazol-2-amine
391.1





8


embedded image


108
5-(1H-pyrazol-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine
378.1





9


embedded image


109
N-(4-morpholinopyridin-2-yl)-6- (1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
379.1





10


embedded image


110
N-(4-morpholinopyridin-2-yl)-5- (1H-pyrazol-4-yl)thiazolo[5,4- b]pyridin-2-amine
380.1





11


embedded image


111
(2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)methanol
324.0





12


embedded image


112
N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
437.1





13


embedded image


113
N-(4- ((dimethylamino)methyl)pyridin- 2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
352.0





14


embedded image


114
N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine
448.1





15


embedded image


115
N-(4-(isopropoxymethyl)pyridin- 2-yl)-6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
366.0





16


embedded image


116
N-(4-((4-(2- methoxyethyl)piperazin-1- yl)methyl)pyridin-2-yl)-5- (pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
462.2





17


embedded image


117
N-(4-((4-(2- methoxyethyl)piperazin-1- yl)methyl)pyridin-2-yl)-5-(1H- pyrazol-4-yl)thiazolo[5,4- b]pyridin-2-amine
451.2





18


embedded image


118
N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-5-(5-methyl-1H- pyrazol-4-yl)thiazolo[5,4- b]pyridin-2-amine
451.2





19


embedded image


119
N-(4-((4-(2- methoxyethyl)piperazin-1- yl)methyl)pyridin-2-yl)-5-(5- methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
465.2





20


embedded image


120
2-methoxy-1-(4-(2-((5-(pyridin- 4-yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanone
462.1





21


embedded image


121
N-(4-(4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine
468.1





22


embedded image


122
2-methoxy-1-(4-((2-((5-(pyridin- 4-yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4- yl)methyl)piperazin-1- yl)ethanone
476.2





23


embedded image


123
2-methoxy-1-(4-(2-((6-(pyridin- 4-yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanone
461.1





24


embedded image


124
N-(4-((4- (methylsulfonyl)piperazin-1- yl)methyl)pyridin-2-yl)-5- (pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
482.1





25


embedded image


125
(S)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-5- (pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
419.1





26


embedded image


126
(R)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-5- (pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
419.1





27


embedded image


127
N-(4-(isopropoxymethyl)pyridin- 2-yl)-6-(pyridin-4- yl)benzo[d]thiazol-2-amine
377.2





28


embedded image


128
N-(4-(isopropoxymethyl)- pyridin-2-yl)-5-(5-methyl-1H- pyrazol-4-yl)thiazolo[5,4- b]pyridin-2-amine
381.1





29


embedded image


129
(S)-N-(4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2-yl)-6- (pyridin-4-yl)benzo[d]thiazol-2- amine
402.1





30


embedded image


130
N-(4-(isopropoxymethyl)pyridin- 2-yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
378.1





31


embedded image


131
5-(1H-pyrazol-4-yl)-N-(4-(4- (3,3,3-trifluoropropyl)piperazin- 1-yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine
475.2





32


embedded image


132
N-(4-(4- (isopropylsulfonyl)piperazin-1- yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
485.1





33


embedded image


133
N-(4-(4- (isopropylsulfonyl)piperazin-1- yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine
496.0





34


embedded image


134
2-methoxy-1-(4-(2-((5- (pyrimidin-5-yl)thiazolo[5,4- b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone
463.1





35


embedded image


135
N-(4-(4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-5-(pyrimidin-5- yl)thiazolo[5,4-b]pyridin-2- amine
469.1





36


embedded image


136
2-((6-methyl-4-(pyrrolidin-3- ylamino)pyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
351.1





37


embedded image


137
N-(4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)-6-(4H- 1,2,4-triazol-4- yl)benzo[d]thiazol-2-amine
378.1





38


embedded image


143
2-((4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
394.95





39


embedded image


144
5-(5-methyl-1H-pyrazol-4-yl)-N- (4-((tetrahydro-2H-pyran-4- yl)oxy)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine
409.1





40


embedded image


146
N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-5-(pyridazin-4- yl)thiazolo[5,4-b]pyridin-2- amine
449.1





41


embedded image


147
1-(4-(2-((5-ethylthiazolo[5,4- b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)-2- methoxyethanone
413.1





42


embedded image


148
1-((2-((5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4- yl)methyl)pyrrolidin-2-one
403.1





43


embedded image


149
1-((2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4- yl)methyl)pyrrolidin-2-one
392.1





44


embedded image


150
2-methoxy-1-(4-(2-((5-(pyridin- 4-yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperidin- 1-yl)ethanone
461.1





45


embedded image


151
N2-(benzo[d]thiazol-2-yl)-N4- (bicyclo[2.2.1]heptan-2-yl)-N6- ((R)-pyrrolidin-3-yl)-1,3,5- triazine-2,4,6-triamine






46


embedded image


152
N2-(bicyclo[2.2.1]heptan-2-yl)- N4-(6-methoxybenzo[d]thiazol- 2-yl)-N6-(pyrrolidin-3-yl)-1,3,5- triazine-2,4,6-triamine






47


embedded image


153
N2-(bicyclo[2.2.1]heptan-2-yl)- N4-(6-chlorobenzo[d]thiazol-2- yl)-N6-(pyrrolidin-3-yl)-1,3,5- triazine-2,4,6-triamine






48


embedded image


154
2-((4-(bicyclo[2.2.1]heptan-2- ylamino)-6-(pyrrolidin-3- ylamino)-1,3,5-triazin-2- yl)amino)benzo[d]thiazole-6- carboxylic acid






49


embedded image


155
N2-(benzo[d]thiazol-2-yl)-N4- ((1R,4S)-bicyclo[2.2.1]heptan- 2-yl)-N6-((R)-pyrrolidin-3- yl)pyrimidine-2,4,6-triamine






50


embedded image


156
2-((6-methoxybenzo[d]thiazol- 2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide
370.1





51


embedded image


157
2-((6-cyanobenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide
365.0





52


embedded image


158
2-((6-chlorobenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide
374.0





53


embedded image


159
(R)-2-((2-((4-(methylamino)-6- (pyrrolidin-3-ylamino)-1,3,5- triazin-2- yl)amino)benzo[d]thiazol-6- yl)oxy)ethanol






54


embedded image


160
(S)-2-((6- methoxybenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide
370.0





55


embedded image


161
(S)-2-((6-cyanobenzo[d]thiazol- 2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide
365.0





56


embedded image


162
(R)-2-((6-cyanobenzo[d]thiazol- 2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide
365.0





57


embedded image


163
(S)-2-((6-chlorobenzo[d]thiazol- 2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide
373.9





58


embedded image


164
(R)-2-((6-chlorobenzo[d]thiazol- 2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide
374.0





59


embedded image


165
N-(2-aminoethyl)-2-((6- cyanobenzo[d]thiazol-2- yl)amino)isonicotinamide
339.0





60


embedded image


166
N-(4-aminobutyl)-2-((6- cyanobenzo[d]thiazol-2- yl)amino)isonicotinamide
367.1





61


embedded image


167
2-((6-cyanobenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3- ylmethyl)isonicotinamide
379.1





62


embedded image


168
2-((6-cyanobenzo[d]thiazol-2- yl)amino)-N-(piperidin-3- yl)isonicotinamide
379.1





63


embedded image


169
2-((6-cyanobenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-2- ylmethyl)isonicotinamide
379.0





64


embedded image


170
2-((4-(3-aminopiperidine-1- carbonyl)pyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
379.0





65


embedded image


171
N2-(6-methoxybenzo[d]thiazol- 2-yl)-N4-(pyrrolidin-3-yl)pyridine- 2,4-diamine
342.0





66


embedded image


172
N2-6-chlorobenzo[d]thiazol-2- yl)-N4-(pyrrolidin-3-yl)pyridine- 2,4-diamine
346.0





67


embedded image


173
(S)-2-((6-bromobenzo[d]thiazol- 2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide
418.0





68


embedded image


174
(S)-2-((6-cyanobenzo[d]thiazol- 2-yl)amino)-N-methyl-N- (pyrrolidin-3-yl)isonicotinamide
379.0





69


embedded image


175
2-((4-(pyrrolidin-3- ylamino)pyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
337.1





70


embedded image


176
(S)-2-((6-(pyridin-4- yl)benzo[d]thiazol-2-yl)amino)- N-(pyrrolidin-3- yl)isonicotinamide
417.1





71


embedded image


177
(S)-2-((6-(pyridin-3- yl)benzo[d]thiazol-2-yl)amino)- N-(pyrrolidin-3- yl)isonicotinamide
417.1





72


embedded image


178
(S)-2-((6-(1-methyl-1H-pyrazol- 4-yl)benzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide
420.1





73


embedded image


179
(S)-2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)amino)- N-(pyrrolidin-3- yl)isonicotinamide
406.2





74


embedded image


180
2-((7-methoxybenzo[d]thiazol- 2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide
370.0





75


embedded image


181
6-bromo-N-(4-(pyrrolidin-1- ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
391.0





76


embedded image


182
(S)-2-((6-cyanobenzo[d]thiazol- 2-yl)amino)-6-methyl-N- (pyrrolidin-3-yl)isonicotinamide
379.1





77


embedded image


183
(S)-2-((7-cyanobenzo[d]thiazol- 2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide
365.0





78


embedded image


184
2-((4-(cyclopentylamino)pyridin- 2-yl)amino)benzo[d]thiazole-6- carbonitrile
336.0





79


embedded image


185
1-(4-((2-((6- bromobenzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)piperazin-1- yl)ethanone
445.9





80


embedded image


186
1-(4-((2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)piperazin-1- yl)ethanone






81


embedded image


187
N-(4-(piperidin-1- ylmethyl)pyridin-2-yl)-6-(1H- pyrazol-4-yl)benzo[d]thiazol-2- amine






82


embedded image


188
2-((5-methyl-4-(pyrrolidin-3- ylamino)pyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
351.1





83


embedded image


189
6-(pyridin-3-yl)-N-(4-(pyrrolidin- 1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine






84


embedded image


190
1-((2-((6-bromobenzo[d]thiazol- 2-yl)amino)pyridin-4- yl)methyl)piperidin-4-ol






85


embedded image


191
2-(((2-((6- bromobenzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)(methyl)amino)ethanol






86


embedded image


192
6-bromo-N-(4- ((dimethylamino)methyl)pyridin- 2-yl)benzo[d]thiazol-2-amine






87


embedded image


193
6-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)amino)- N-(pyrrolidin-3-yl)picolinamide
406.1





88


embedded image


194
6-(1H-pyrazol-5-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine






89


embedded image


195
2-((4-((2- aminopropyl)amino)pyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
325.1





90


embedded image


196
2-((4-((1-aminopropan-2- yl)amino)pyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
325.1





91


embedded image


197
N-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)methanesulfonamide
412.1





92


embedded image


198
N-(4-(piperidin-1- ylmethyl)pyridin-2-yl)-6-(pyridin- 4-yl)benzo[d]thiazol-2-amine
402.1





93


embedded image


199
N-(4- ((dimethylamino)methyl)pyridin- 2-yl)-6-(pyridin-4- yl)benzo[d]thiazol-2-amine
362.1





94


embedded image


200
4-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)amino)- N-(pyrrolidin-3-yl)picolinamide
406.1





95


embedded image


201
6-(6-methoxypyridin-3-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
418.2





96


embedded image


202
N-(4-(4-methylpiperazin-1- yl)pyridin-2-yl)-6-(pyridin-4- yl)benzo[d]thiazol-2-amine
403.1





97


embedded image


203
6-(pyrimidin-5-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
389.1





98


embedded image


204
N-(4-((4-methylpiperazin-1- yl)methyl)pyridin-2-yl)-6- (pyridin-4-yl)benzo[d]thiazol-2- amine
417.1





99


embedded image


205
6-(2-methylpyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
402.1





100


embedded image


206
2-(2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)acetic acid
363.0





101


embedded image


207
1,1-dimethyl-3-((2-((6-(pyridin- 4-yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)urea
405.1





102


embedded image


208
6-(3-methoxypyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
418.1





103


embedded image


209
6-(2-methoxypyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
418.1





104


embedded image


210
6-(2-chloropyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
422.0





105


embedded image


211
6-(3-methylpyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
402.1





106


embedded image


212
2-(2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)-N-(2- (pyrrolidin-1-yl)ethyl)acetamide
459.1





107


embedded image


213
N-(4- ((methylamino)methyl)pyridin-2- yl)-6-(pyridin-4- yl)benzo[d]thiazol-2-amine
348.1





108


embedded image


214
3-(2-((4-(pyrrolidin-1- ylmethyl)pyridin-2- yl)amino)benzo[d]thiazol-6- yl)benzonitrile
412.1





109


embedded image


215
N-(4-morpholinopyridin-2-yl)-6- (pyridin-4-yl)benzo[d]thiazol-2- amine
390.1





110


embedded image


216
N-(4-((3-methoxypyrrolidin-1- yl)methyl)pyridin-2-yl)-6- (pyridin-4-yl)benzo[d]thiazol-2- amine
418.1





111


embedded image


217
N-(4-((4- (methylsulfonyl)piperazin-1- yl)methyl)pyridin-2-yl)-6- (pyridin-4-yl)benzo[d]thiazol-2- amine
481.0





112


embedded image


218
6-(2-methoxypyrimidin-5-yl)-N- (4-(pyrrolidin-1-ylmethyl)pyridin- 2-yl)benzo[d]thiazol-2-amine
419.1





113


embedded image


219
3-(piperidin-1-yl)-N-((2-((6- (pyridin-4-yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)propanamide
473.2





114


embedded image


220
6-(benzo[c][1,2,5]oxadiazol-5- yl)-N-(4-(pyrrolidin-1- ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
429.1





115


embedded image


221
1-methyl-4-(2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)piperazin- 2-one
417.1





116


embedded image


222
2-(4-(2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanol
433.1





117


embedded image


223
N-methyl-4-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)piperazine-1- carboxamide
460.2





118


embedded image


224
Methyl 2-(2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)acetate
377.1





119


embedded image


225
2-(methyl(2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)amino)ethanol
378.1





120


embedded image


226
1-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)pyrrolidin-3-ol
404.1





121


embedded image


227
N-(4-((4-methylpiperazin-1- yl)methyl)pyridin-2-yl)-6- (pyrimidin-5-yl)benzo[d]thiazol- 2-amine
418.2





123


embedded image


228
2-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)amino)ethanol
364.1





124


embedded image


229
7-methyl-6-(pyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
402.1





125


embedded image


230
5-methyl-6-(pyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
402.1





126


embedded image


231
N-(pyridin-2-yl)-6-(pyridin-4- yl)benzo[d]thiazol-2-amine
305.0





127


embedded image


232
6-(2-aminopyrimidin-5-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
404.1





128


embedded image


233
2-(2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)-1- (pyrrolidin-1-yl)ethanone
416.1





129


embedded image


234
N-(4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)-6-(2- (trifluoromethyl)pyridin-4- yl)benzo[d]thiazol-2-amine
456.1





130


embedded image


235
1-methyl-N-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)pyrrolidine-2- carboxamide
445.1





131


embedded image


236
5-(pyridin-4-yl)-N-(4-(pyrrolidin- 1-ylmethyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine
389.1





132


embedded image


237
5-(pyrimidin-5-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine
390.1





133


embedded image


238
N-(4-(aminomethyl)pyridin-2-yl)- 6-(pyrimidin-5- yl)benzo[d]thiazol-2-amine
335.1





134


embedded image


239
N-methyl-2-(2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)acetamide
376.1





135


embedded image


240
N-(2-hydroxyethyl)-2-(2-((6- (pyridin-4-yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)acetamide
406.0





136


embedded image


242
N-(4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)-6-(1H- 1,2,4-triazol-1- yl)benzo[d]thiazol-2-amine
378.1





137


embedded image


243
1-(3-hydroxypyrrolidin-1-yl)-2- (2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)ethanone
432.0





138


embedded image


244
N-((2-((6-(pyrimidin-5- yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)methanesulfonamide
413.0





139


embedded image


245
N-(4-morpholinopyridin-2-yl)-6- (4H-1,2,4-triazol-4- yl)benzo[d]thiazol-2-amine
380.1





140


embedded image


246
N-(4-(4-methylpiperazin-1- yl)pyridin-2-yl)-6-(4H-1,2,4- triazol-4-yl)benzo[d]thiazol-2- amine
393.2





141


embedded image


247
N-(4-(piperazin-1-yl)pyridin-2- yl)-6-(pyridin-4- yl)benzo[d]thiazol-2-amine
389.1





142


embedded image


248
N-(4-(4-methylpiperazin-1- yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
393.0





143


embedded image


249
N-(4-(piperazin-1-yl)pyridin-2- yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
379.1





144


embedded image


250
6-(1H-imidazol-1-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
377.2





145


embedded image


251
6-(5-methyl-1H-pyrazol-4-yl)-N- (4-morpholinopyridin-2- yl)benzo[d]thiazol-2-amine
393.1





146


embedded image


252
6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-methylpiperazin-1- yl)pyridin-2-yl)benzo[d]thiazol- 2-amine
406.1





147


embedded image


253
N-(4-(piperazin-1-yl)pyridin-2- yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
390.1





148


embedded image


254
N-(4-(pyrrolidin-3- ylamino)pyridin-2-yl)-6- cyanobenzo[d]thiazol-2-amine






149


embedded image


255
N-(4-(4-methylpiperazin-1- yl)pyridin-2-yl)-6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
392.1





150


embedded image


256
N-(4-morpholinopyridin-2-yl)-5- (pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
391.0





151


embedded image


257
N-(4-(4-methylpiperazin-1- yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine
404.0





152


embedded image


258
N-(4-(piperazin-1-yl)pyridin-2- yl)-6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
378.0





153


embedded image


259
6-(pyridazin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
389.0





154


embedded image


260
N-(4- ((methylamino)methyl)pyridin-2- yl)-6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
337.0





155


embedded image


261
N-(4- ((dimethylamino)methyl)pyridin- 2-yl)-6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
351.1





156


embedded image


262
N-(pyrazin-2-yl)-6-(pyridin-4- yl)benzo[d]thiazol-2-amine
306.0





157


embedded image


263
N-(4-(azetidin-1- ylmethyl)pyridin-2-yl)-6-(1H- pyrazol-4-yl)benzo[d]thiazol-2- amine
363.0





158


embedded image


264
N-(4-(4-methyl-1,4-diazepan-1- yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
407.1





159


embedded image


265
N-(4-(4-benzylpiperazin-1- yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
469.1





160


embedded image


266
5-(2-((4-(pyrrolidin-1- ylmethyl)pyridin-2- yl)amino)thiazolo[5,4-b]pyridin- 5-yl)pyrimidine-2-carbonitrile
415.0





161


embedded image


267
1-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)-2- (dimethylamino)ethanone
464.0





162


embedded image


268
2-hydroxy-N-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)acetamide
392.0





163


embedded image


269
2-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanol
423.1





164


embedded image


270
1-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)-2-methoxyethanone
451.1





165


embedded image


271
5-(2-((4-(pyrrolidin-1- ylmethyl)pyridin-2- yl)amino)benzo[d]thiazol-6- yl)pyrimidine-2-carbonitrile
414.0





166


embedded image


272
(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)methanol
325.0





167


embedded image


273
N2-(6-(pyridin-4- yl)benzo[d]thiazol-2-yl)pyridine- 2,6-diamine
320.0





168


embedded image


274
6-(1H-pyrrol-3-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
376.1





169


embedded image


275
1-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)-2-hydroxyethanone
437.1





170


embedded image


276
N-(4- ((methylamino)methyl)pyridin-2- yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
338.0





171


embedded image


277
N-(4-(aminomethyl)pyridin-2-yl)- 5-(1H-pyrazol-4-yl)thiazolo[5,4- b]pyridin-2-amine
324.0





172


embedded image


278
1-(2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)ethanol
338.0





173


embedded image


279
N-(4-(4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
457.1





174


embedded image


280
2-(2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)propan-2- ol
352.0





175


embedded image


281
N-(4-(methoxymethyl)pyridin-2- yl)-6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
338.0





176


embedded image


282
1-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)-3-(dimethylamino)propan- 1-one
478.2





177


embedded image


283
(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)-3-fluoropyridin-4- yl)methanol
343.0





178


embedded image


284
1-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)-3-(pyrrolidin-1-yl)propan-1- one
504.2





179


embedded image


285
N-(4- ((dimethylamino)methyl)pyridin- 2-yl)-6-(5-methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
365.1





180


embedded image


286
6-(5-methyl-1H-pyrazol-4-yl)- N-(4- ((methylamino)methyl)pyridin-2- yl)benzo[d]thiazol-2-amine
351.1





181


embedded image


287
N-(4-(aminomethyl)pyridin-2-yl)- 6-(5-methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
337.0





182


embedded image


288
6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(piperidin-1-ylmethyl)pyridin- 2-yl)benzo[d]thiazol-2-amine
405.1





183


embedded image


289
6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(morpholinomethyl)pyridin-2- yl)benzo[d]thiazol-2-amine
407.2





184


embedded image


290
N-(4- ((dimethylamino)methyl)pyridin- 2-yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
366.1





185


embedded image


291
5-(5-methyl-1H-pyrazol-4-yl)-N- (4-(piperidin-1-ylmethyl)pyridin- 2-yl)thiazolo[5,4-b]pyridin-2- amine
406.1





186


embedded image


292
5-(5-methyl-1H-pyrazol-4-yl)-N- (4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine
406.1





187


embedded image


293
N-(4-(isoindolin-2- ylmethyl)pyridin-2-yl)-5-(5- methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
440.1





188


embedded image


294
N-(4-((3-methoxypyrrolidin-1- yl)methyl)pyridin-2-yl)-5-(5- methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
422.2





189


embedded image


295
5-(5-methyl-1H-pyrazol-4-yl)-N- (4-(morpholinomethyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine
408.1





190


embedded image


296
N-(4-(aminomethyl)pyridin-2-yl)- 6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
323.1





191


embedded image


297
5-(5-methyl-1H-pyrazol-4-yl)- N-(4- ((methylamino)methyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine
352.1





192


embedded image


298
N-(4-(azepan-1- ylmethyl)pyridin-2-yl)-5-(5- methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
420.1





193


embedded image


299
N-(4-(((1S,4R)- bicyclo[2.2.1]heptan-2- ylamino)methyl)pyridin-2-yl)-5- (5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
432.2





194


embedded image


300
5-(5-methyl-1H-pyrazol-4-yl)-N- (4-((3-phenylpyrrolidin-1- yl)methyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine
468.1





195


embedded image


301
N-(4-(azepan-1- ylmethyl)pyridin-2-yl)-6-(5- methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
419.2





196


embedded image


302
6-(5-methyl-1H-pyrazol-4-yl)-N- (4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2- yl)benzo[d]thiazol-2-amine
405.2





197


embedded image


303
N-(4-(isoindolin-2- ylmethyl)pyridin-2-yl)-6-(5- methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
439.1





198


embedded image


304
N-(4-((3-methoxypyrrolidin-1- yl)methyl)pyridin-2-yl)-6-(5- methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
421.2





199


embedded image


305
1-((2-((6-(5-methyl-1H-pyrazol- 4-yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)pyrrolidin-3-ol
407.1





200


embedded image


306
N-(4-(azetidin-1- ylmethyl)pyridin-2-yl)-5-(5- methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
378.1





201


embedded image


307
1-((2-((5-(5-methyl-1H-pyrazol- 4-yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4- yl)methyl)pyrrolidin-3-ol
408.1





202


embedded image


308
N-(4-(azetidin-1- ylmethyl)pyridin-2-yl)-6-(5- methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
377.1





203


embedded image


309
6-(5-methyl-1H-pyrazol-4-yl)-N- (4-((3-phenylpyrrolidin-1- yl)methyl)pyridin-2- yl)benzo[d]thiazol-2-amine
467.1





204


embedded image


310
N-(4-((4-(2- methoxyethyl)piperazin-1- yl)methyl)pyridin-2-yl)-6-(5- methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
464.1





205


embedded image


311
N-(4-((4-(2- methoxyethyl)piperazin-1- yl)methyl)pyridin-2-yl)-6- (pyridin-4-yl)benzo[d]thiazol-2- amine
461.2





206


embedded image


312
N-(4-((4-(2- methoxyethyl)piperazin-1- yl)methyl)pyridin-2-yl)-6-(1H- pyrazol-4-yl)benzo[d]thiazol-2- amine
450.2





207


embedded image


313
6-(5-methyl-1H-pyrazol-4-yl)-N- (4-((4-(methylsulfonyl)piperazin- 1-yl)methyl)pyridin-2- yl)benzo[d]thiazol-2-amine
484.0





208


embedded image


314
N-(4-(aminomethyl)pyridin-2-yl)- 5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
338.1





209


embedded image


315
N-(4-((1S,4R)-2- azabicyclo[2.2.1]heptan-2- ylmethyl)pyridin-2-yl)-5-(5- methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
418.1





210


embedded image


316
N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-6-(5-methyl-1H- pyrazol-4-yl)benzo[d]thiazol-2- amine
450.1





211


embedded image


317
2-methoxy-1-(4-(2-((6-(5- methyl-1H-pyrazol-4-yl) thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanone
465.0





212


embedded image


318
N-(4-((1S,4R)-2- azabicyclo[2.2.1]heptan-2- ylmethyl)pyridin-2-yl)-6-(5- methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine






213


embedded image


319
N-(4-(((1S,4R)- bicyclo[2.2.1]heptan-2- ylamino)methyl)pyridin-2-yl)-6- (5-methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine






214


embedded image


320
N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
436.1





215


embedded image


321
N-(4-((3,3-dimethylpyrrolidin-1- yl)methyl)pyridin-2-yl)-5-(5- methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
420.2





216


embedded image


322
N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-6-(pyridin-4- yl)benzo[d]thiazol-2-amine
447.1





217


embedded image


323
5-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-(methylsulfonyl)piperazin- 1-yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine
471.1





218


embedded image


324
N-(4-((3,3-dimethylpyrrolidin-1- yl)methyl)pyridin-2-yl)-6-(5- methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
419.2





219


embedded image


325
2-methoxy-1-(4-((2-((6-(5- methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)piperazin-1- yl)ethanone
478.2





220


embedded image


326
6-(1H-pyrazol-4-yl)-N-(4- ((pyridin-3-yloxy)methyl)pyridin- 2-yl)benzo[d]thiazol-2-amine
401.0





221


embedded image


327
N-(4-(4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-6-(pyridin-4- yl)benzo[d]thiazol-2-amine
467.1





222


embedded image


328
N-(4-(4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
456.1





223


embedded image


329
N-(4-((4- (methylsulfonyl)piperazin-1- yl)methyl)pyridin-2-yl)-6-(1H- pyrazol-4-yl)benzo[d]thiazol-2- amine
470.1





224


embedded image


330
N-(4-((4- (methylsulfonyl)piperazin-1- yl)methyl)pyridin-2-yl)-5-(1H- pyrazol-4-yl)thiazolo[5,4- b]pyridin-2-amine
471.1





225


embedded image


331
2-methoxy-1-(4-(2-((6-(5- methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanone
464.2





226


embedded image


332
2-methoxy-1-(4-((2-((6-(pyridin- 4-yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)piperazin-1- yl)ethanone
475.2





227


embedded image


334
1-(4-((2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)piperazin-1-yl)-2- methoxyethanone
464.2





228


embedded image


335
2-methoxy-1-(4-((2-((5-(5- methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4- yl)methyl)piperazin-1- yl)ethanone
479.2





229


embedded image


336
1-(4-((2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4- yl)methyl)piperazin-1-yl)-2- methoxyethanone
465.2





230


embedded image


337
6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-(methylsulfonyl)piperazin- 1-yl)pyridin-2- yl)benzo[d]thiazol-2-amine
470.1





231


embedded image


338
1-(4-(2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)-2-methoxyethanone
450.1





232


embedded image


339
4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)-1- methylpiperazin-2-one
407.1





233


embedded image


340
5-(5-methyl-1H-pyrazol-4-yl)-N- (4-((4-(methylsulfonyl)piperazin- 1-yl)methyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine
485.1





234


embedded image


341
6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(piperazin-1-yl)pyridin-2- yl)benzo[d]thiazol-2-amine






235


embedded image


342
1-((2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)pyrrolidin-3-ol
393.1





236


embedded image


343
(R)-6-(5-methyl-1H-pyrazol-4- yl)-N-(4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2- yl)benzo[d]thiazol-2-amine
405.1





237


embedded image


344
(R)-5-(5-methyl-1H-pyrazol-4- yl)-N-(4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine
406.1





238


embedded image


345
(S)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-6-(5- methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
421.1





239


embedded image


346
(R)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-6-(5- methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
421.1





240


embedded image


347
(S)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-5-(5- methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
422.1





241


embedded image


348
(R)-N-(4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2-yl)-5- (pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
403.2





242


embedded image


349
N-(4-(isopropoxymethyl)pyridin- 2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
367.0





243


embedded image


350
(S)-6-(5-methyl-1H-pyrazol-4- yl)-N-(4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2- yl)benzo[d]thiazol-2-amine
405.1





244


embedded image


351
(R)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-5-(5- methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
422.1





245


embedded image


352
(R)-N-(4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2-yl)-6- (pyridin-4-yl)benzo[d]thiazol-2- amine
402.1





246


embedded image


353
(S)-N-(4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2-yl)-5- (pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
403.1





247


embedded image


354
(S)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-6- (pyridin-4-yl)benzo[d]thiazol-2- amine
418.1





248


embedded image


355
(R)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-6- (pyridin-4-yl)benzo[d]thiazol-2- amine
418.1





249


embedded image


356
N-(4- ((cyclopentyloxy)methyl)pyridin- 2-yl)-6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
392.1





250


embedded image


357
6-(1H-pyrazol-4-yl)-N-(4- (((tetrahydro-2H-pyran-4- yl)oxy)methyl)pyridin-2- yl)benzo[d]thiazol-2-amine
408.1





251


embedded image


358
(S)-5-(5-methyl-1H-pyrazol-4- yl)-N-(4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine
406.1





252


embedded image


359
N-(4-(isopropoxymethyl)pyridin- 2-yl)-6-(5-methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
380.1





253


embedded image


360
N-(4-(4-(2- isopropoxyethyl)piperazin-1- yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
465.2





254


embedded image


361
5-(pyridin-4-yl)-N-(4-(4-(3,3,3- trifluoropropyl)piperazin-1- yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine
486.2





255


embedded image


362
N-(4-(4-(2- isopropoxyethyl)piperazin-1- yl)pyridin-2-yl)-5-(5-methyl-1H- pyrazol-4-yl)thiazolo[5,4- b]pyridin-2-amine
479.2





256


embedded image


363
5-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-(3,3,3- trifluoropropyl)piperazin-1- yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine
489.0





257


embedded image


364
N-(4-(4-(2- isopropoxyethyl)piperazin-1- yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine
476.2





258


embedded image


365
N-(4-(4-(1-methoxypropan-2- yl)piperazin-1-yl)pyridin-2-yl)-5- (5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
465.1





259


embedded image


366
6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-(3,3,3- trifluoropropyl)piperazin-1- yl)pyridin-2-yl)benzo[d]thiazol- 2-amine
488.1





260


embedded image


367
(S)-N-(4-(3-methyl-4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine
482.1





261


embedded image


368
N-(4-(4-(2- isopropoxyethyl)piperazin-1- yl)pyridin-2-yl)-6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine
464.1





262


embedded image


369
N-(4-(4- (isopropylsulfonyl)piperazin-1- yl)pyridin-2-yl)-5-(5-methyl-1H- pyrazol-4-yl)thiazolo[5,4- b]pyridin-2-amine
499.2





263


embedded image


370
2,2-dimethyl-1-(4-(2-((5-(5- methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)propan-1-one
477.1





264


embedded image


371
N-(4-(4-(2- isopropoxyethyl)piperazin-1- yl)pyridin-2-yl)-6-(pyridin-4- yl)benzo[d]thiazol-2-amine
475.2





265


embedded image


372
6-(pyridin-4-yl)-N-(4-(4-(3,3,3- trifluoropropyl)piperazin-1- yl)pyridin-2-yl)benzo[d]thiazol- 2-amine
485.1





266


embedded image


373
(S)-2-methoxy-1-(2-methyl-4-(2- ((5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanone
479.2





267


embedded image


374
(S)-2-methoxy-1-(2-methyl-4-(2- ((5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone
476.1





268


embedded image


375
(S)-5-(5-methyl-1H-pyrazol-4- yl)-N-(4-(3-methyl-4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine
485





269


embedded image


376
(R)-N-(4-(4-(2-methoxyethyl)-3- methylpiperazin-1-yl)pyridin-2- yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
465.1





270


embedded image


377
6-(1H-pyrazol-4-yl)-N-(4-(4- (3,3,3-trifluoropropyl)piperazin- 1-yl)pyridin-2- yl)benzo[d]thiazol-2-amine
474.1





271


embedded image


378
N-(4-(4-(2- isopropoxyethyl)piperazin-1- yl)pyridin-2-yl)-6-(5-methyl-1H- pyrazol-4-yl)benzo[d]thiazol-2- amine
478.2





272


embedded image


379
(R)-2-methoxy-1-(3-methyl-4-(2- ((5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanone
479.2





273


embedded image


380
(R)-N-(4-(2-methyl-4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine
482.1





274


embedded image


381
(S)-N-(4-(4-(2-methoxyethyl)-3- methylpiperazin-1-yl)pyridin-2- yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
465.2





275


embedded image


382
(S)-N-(4-(4-(2-methoxyethyl)-3- methylpiperazin-1-yl)pyridin-2- yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
462.1





276


embedded image


383
(R)-N-(4-(4-(2-methoxyethyl)-3- methylpiperazin-1-yl)pyridin-2- yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
462.1





277


embedded image


384
1-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)-2-isopropoxyethanone
479.1





278


embedded image


385
2-isopropoxy-1-(4-(2-((5-(5- methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanone
493.1





279


embedded image


386
2-isopropoxy-1-(4-(2-((5- (pyridin-4-yl)thiazolo[5,4- b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone
490.1





280


embedded image


387
(R)-2-methoxy-1-(3-methyl-4-(2- ((5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone
476.1





281


embedded image


388
(R)-5-(5-methyl-1H-pyrazol yl)-N-(4-(2-methyl-4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine
485.1





282


embedded image


389
(R)-2-methoxy-1-(2-methyl-4-(2- ((5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanone
479.2





283


embedded image


390
(R)-2-methoxy-1-(2-methyl-4-(2- ((5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone
476.1





284


embedded image


391
2-methoxy-1-(4-(2-((5-(2- methylpyridin-4-yl)thiazolo[5,4- b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone
476.1





285


embedded image


392
(R)-N-(4-(3-methyl-4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine
482.0





286


embedded image


393
(S)-5-(5-methyl-1H-pyrazol-4- yl)-N-(4-(3-methyl-4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine
485.1





287


embedded image


394
N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-5-(2- methylpyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
462.1





288


embedded image


395
5-(2-methylpyridin-4-yl)-N-(4-(4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine
482.0





289


embedded image


396
2-methoxy-1-(4-(2-((5- (pyridazin-4-yl)thiazolo[5,4- b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone
463.0





290


embedded image


397
N-(4-(4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-5-(pyridazin-4- yl)thiazolo[5,4-b]pyridin-2- amine
469.1





291


embedded image


398
(S)-N-(4-(4-(2-methoxyethyl)-2- methylpiperazin-1-yl)pyridin-2- yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
462.1





292


embedded image


399
(S)-N-(4-(4-(2-methoxyethyl)-2- methylpiperazin-1-yl)pyridin-2- yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
465.1





293


embedded image


400
(R)-N-(4-(4-(2-methoxyethyl)-2- methylpiperazin-1-yl)pyridin-2- yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
462.1





294


embedded image


401
N-(4-(4-(2- methoxyethyl)piperidin-1- yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine
447.1





295


embedded image


402
N-(4-(4-(2- methoxyethyl)piperidin-1- yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
436.1





296


embedded image


403
N4-(2-methoxyethyl)-N4-methyl- N2-(5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-yl)pyridine-2,4- diamine
393.1





297


embedded image


404
N-(4-((1S,4S)-5-(2- methoxyethyl)-2,5- diazabicyclo[2.2.1]heptan-2- yl)pyridin-2-yl)-5-(5-methyl-1H- pyrazol-4-yl)thiazolo(5,4- b]pyridin-2-amine
463.1





298


embedded image


405
5-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-(pyridin-2-yl)piperazin-1- yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine
470.2





299


embedded image


406
N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-5-(pyrimidin-5- yl)thiazolo[5,4-b]pyridin-2- amine
449.1





300


embedded image


407
N-(4-(4-(2- methoxyethyl)piperidin-1- yl)pyridin-2-yl)-5-(5-methyl-1H- pyrazol-4-yl)thiazolo[5,4- b]pyridin-2-amine
450.1





301


embedded image


408
N4-(2-methoxyethyl)-N4-methyl- N2-(5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- yl)pyridine-2,4-diamine
396.1





302


embedded image


409
N2-(5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)- N4-(2-methoxyethyl)-N4- methylpyridine-2,4-diamine
382.0





303


embedded image


410
(R)-N-(4-(4-(2-methoxyethyl)-2- methylpiperazin-1-yl)pyridin-2- yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine
465.2





304


embedded image


411
(S)-N-(4-(2-methyl-4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine
482.0





305


embedded image


412
(S)-5-(5-methyl-1H-pyrazol-4- yl)-N-(4-(2-methyl-4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)thiazolo(5,4- b]pyridin-2-amine
485.1





306


embedded image


413
2-((4-morpholinopyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
337.9





307


embedded image


414
2-((4-(pyrrolidine-1- carbonyl)pyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
349.9





308


embedded image


415
(2-((5-bromothiazolo[5,4- b]pyridin-2-yl)amino)pyridin-4- yl)(pyrrolidin-1-yl)methanone
403.78





309


embedded image


416
N-(4-(cyclopentyloxy)pyridin-2- yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine
390.0





310


embedded image


417
N-(4-(cyclopentyloxy)pyridin-2- yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridine-2- amine
393.1





311


embedded image


418
5-ethynyl-N-(4-(pyrrolidin-1- ylmethyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine
336.0





312


embedded image


419
N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-6- methylbenzo[d]thiazol-2-amine
384.02





313


embedded image


420
2-((4,6-dimethylpyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
281.02





314


embedded image


421
2-((4-(1,4-dioxa-8- azaspiro[4.5]decan-8-yl)pyridin- 2-yl)amino)benzo[d]thiazole-6- carbonitrile
394.0





315


embedded image


422
2-((4-(4-oxopiperidin-1- yl)pyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
349.97





316


embedded image


423
N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)- [1,3]dioxolo[4′,5′:4,5]benzo[1,2- d]thiazol-6-amine
415.92





317


embedded image


424
6-isopropyl-N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)benzo[d]thiazol- 2-amine
412.01





318


embedded image


425
2-((4-(4-hydroxypiperidin-1- yl)pyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
351.92





319


embedded image


426
2-((4-(2-methoxyethoxy)pyridin- 2-yl)amino)benzo[d]thiazole-6- carbonitrile
326.91





320


embedded image


427
2-((4-isobutoxypyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
324.96





321


embedded image


428
N-(4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)-5- vinylthiazolo[5,4-b]pyridin-2- amine






322


embedded image


429
5-ethyl-N-(4-(pyrrolidin-1- ylmethyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine






323


embedded image


430
5-(pyridin-4-yl)-N-(4- ((tetrahydro-2H-pyran-4- yl)oxy)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine
406.1





324


embedded image


431
N-(4-ethylpyridin-2-yl)-6-(1H- imidazol-4-yl)benzo[d]thiazol-2- amine
321.92





325


embedded image


432
1-(4-(2-((5-ethynylthiazolo[5,4- b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)-2- methoxyethanone
409.0





326


embedded image


433
4-(2-((5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)morpholin- 3-one
405.1





327


embedded image


434
2-((4-ethylpyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
280.95





328


embedded image


435
1,1-dimethyl-3-(2-((5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)urea
392.1





329


embedded image


436
5-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-(tetrahydro-2H-pyran-4- yl)piperazin-1-yl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine
477.1





330


embedded image


437
Methyl (2-((5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)carbamate
379.1





331


embedded image


438
2-((4-(hydroxymethyl)pyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile
283.0





332


embedded image


439
5-cyclopropyl-N-(4-(pyrrolidin-1- ylmethyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine
352.1









Example 333
Synthesis of N-(4-ethylpyridin-2-yl)-6-(oxazol-5-yl)benzo[d]thiazol-2-amine (Compound 501, Structure 4 in Scheme II R1=ethyl, R4=5-oxazolyl)



embedded image


A mixture of 4-ethylpyridin-2-amine (100 mg, 0.821 mmol) and bis(1-benzotriazolyl)methanethione (250 mg, 0.891 mmol) were dissolved in 5 mL of anhydrous N,N-dimethylacetamide. The solution was stirred at room temperature for 1 hour. 4-(Oxazol-5-yl)aniline (130 mg, 0.821 mmol) was the added and the solution stirred at 50° C. for an additional hour. Water (15 mL) was then added and the resulting precipitate collected by vacuum filtration and dried under vacuum. The resulting tan powder was used without further purification. MS calculated for C17H16N4OS: 325.1045; [M+H]+. found: 324.89.




embedded image


1-(4-Ethylpyridin-2-yl)-3-(4-(oxazol-5-yl)phenyl)thiourea (0.27 g, 0.8 mmol) was dissolved in 5 mL of acetic acid. Benzyltrimethylammonium tribromide (320 mg, 0.821 mmol) was then added directly. The mixture was stirred at 50° C. for 1 hour. The mixture was cooled to 0° C. and diluted with 15 mL of water. The resulting solution was then made basic through addition of solid KOH pellets. The resulting precipitate was collected by vacuum filtration, washed with water and dried under vacuum to afford the crude product as a tan solid. A portion of the solid was purified by rp-HPLC affording 0.6 mg of N-(4-ethylpyridin-2-yl)-6-(oxazol-5-yl)benzo[d]thiazol-2-amine 501 as a yellow solid. MS calculated for C17H14N4OS: 323.0888; [M+H]+. found: 322.93. 1H-NMR (400 MHz, MeOD) 8.25-8.23 (m, 2H), 8.17 (s, 1H), 7.75 (d, J=8.4, 1H), 7.66 (d, J=8.4, 1H) 7.50 (s, 1H), 6.97 (s, 1H), 6.88 (d, J=8.4, 1H), 2.68 (q, J=7.7, 2H), 1.28 (t, J=7.7, 3H).


Example 334
Synthesis of 6-(1H-pyrazol-4-yl)-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-1)imidazo[1,2-a]pyridin-2-amine (Compound 493, structure 10 in Scheme III R1═CH2—N-pyrrolidinyl, R4=4-pyrazolyl)



embedded image


To a solution of 6-bromoimidazo[1,2-a]pyridin-2-amine (200 mg; 0.94 mmol) in dry THF (4 mL) was added NaH (90 mg; 3.76 mmol) in portions at 0° C. The reaction mixture was stirred at r.t. for half an hour. Then 2-chloro-4-(pyrrolidin-1-ylmethyl)pyridine (222 mg, 1.1 mmol) was added. The mixture was heated to 120° C. for 24 hrs. The mixture was quenched by addition of H2O (20 mL) slowly at 0° C., extracted with DCM (30 mL×3). The combined organic phases were concentrated under reduced pressure and purified by column chromatography on silica (DCM:MeOH=15:1) to obtain 6-bromo-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-amine (110 mg, yield 80%) as a brown solid.




embedded image


To a solution of 6-bromo-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-amine (50 mg, 0.13 mmol) in mixed dioxane/H2O (2 mL/0.5 mL) was added the pinacol boronate ester (59.2 mg, 0.2 mmol), K2CO3 (55.6 mg, 0.4 mmol) and Pd(dppf)Cl2 (10.8 mg, 0.013 mmol) under nitrogen atmosphere. The mixture reacted under microwave condition at 140° C. for 2 hrs. After cooling, the solvent was removed under reduced pressure, and the residue was purified by prep-TLC to afford 6-(1H-pyrazol-4-yl)-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-amine 493 (8.5 mg, yield 17.7%). 1H NMR (400 MHz MeOD) δ 8.93 (s, 1H), 8.47-8.45 (d, J=5.2, 1H), 8.12 (s, 2H), 8.06-8.03 (dd, J=9.2, 1H), 7.85-7.82 (dd, J=9.6, 1H), 7.14-7.11 (m, 2H), 4.43 (s, 2H), 3.55-3.30 (m, 4H), 2.14 (s, 4H).


Examples 335-352

Compounds 484-502 were prepared in a similar fashion as described in Examples 333-334 and their structures, names, and found molecular mass ion numbers are summarized in Table 2 (Example: E.g.; Compound: Cmpd).













TABLE 2





E.g.
Structure
Cmpd
Name
[M + H]+







335


embedded image


484
2-((4-(hydoxymethyl)pyridin-2- yl)amino)imidazo[1,2-a]pyridine-6- carbonitrile






336


embedded image


485
(S)-tert-butyl 3-(2-((6- cyanoimidazo[1,2-a]pyridin-2- yl)amino)isonicotinamido)pyrrolidine- 1-carboxylate
448.2





337


embedded image


486
(S)-2-((6-cyanoimidazo[1,2-a]pyridin- 2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide
348.2





338


embedded image


487
2-((4-(pyrrolidin-1-ylmethyl)pyridin-2- yl)amino)imidazo[1,2-a]pyridine-6- carbonitrile
319.2





339


embedded image


488
6-(pyridin-3-yl)-N-(4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)imidazo[1,2- a]pyridin-2-amine
371.1





340


embedded image


489
1-(4-((2-((6-(pyridin-4-yl)imidazo[1,2- a]pyridin-2-yl)amino)pyridin-4- yl)methyl)piperazin-1-yl)ethanone
428.1





341


embedded image


490
1-(4-((2-((6-(pyridin-3-yl)imidazo[1,2- a]pyridin-2-yl)amino)pyridin-4- yl)methyl)piperazin-1-yl)ethanone
428.1





342


embedded image


491
(2-((6-(pyridin-4-yl)imidazo[1,2- a]pyridin-2-yl)amino)pyridin-4- yl)methanol
318.1





343


embedded image


492
N-(4-(piperazin-1-ylmethyl)pyridin-2- yl)-6-(pyridin-4-yl)imidazo[1,2- a]pyridin-2-amine
386.1





345


embedded image


494
1-(4-((2-((6-(1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-2- yl)amino)pyridin-4-yl)methyl)piperazin- 1-yl)ethanone
417.7





346


embedded image


495
N-(4-(piperazin-1-ylmethyl)pyridin-2- yl)-6-(1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-2-amine
375.1





347


embedded image


496
(2-((6-(1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-2-yl)amino)pyridin-4- yl)methanol
307.1





348


embedded image


497
N-(4-(4-(methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-6-(pyridin-4- yl)imidazo[1,2-a]pyridin-2-amine
450.1





349


embedded image


498
2-methoxy-1-(4-(2-((6-(pyridin-4- yl)imidazo[1,2-a]pyridin-2- yl)amino)pyridin-4-yl)piperazin-1- yl)ethanone
444.2





350


embedded image


499
N-(4-(4-(methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-6-(1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-2-amine
439.1





351


embedded image


500
6-(5-methyl-1H-pyrazol-4-yl)-N-(4-(4- (methylsulfonyl)piperazin-1-yl)pyridin- 2-yl)imidazo[1,2-a]pyridin-2-amine
453.1





352


embedded image


502
(2-((6-(pyridin-3-yl)imidazo[1,2- a]pyridin-2-yl)amino)pyridin-4- yl)methanol
318.0









Examples 353-430

Compounds 503-580 were prepared in a similar fashion as described in Examples 1-2 and 333-334, and their structures and names are summarized in Table 3 (Example E.g.; Compound: Cmpd).












TABLE 3





E.g.
Structure
Cmpd
Name







353


embedded image


503
3-((5-trifluoromethylbenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)benzamide





354


embedded image


504
3-((6-nitrobenzo[d]thiazol-2-yl)amino)-N- (pyrrolidin-3-yl)benzamide





355


embedded image


505
2-(3-(pyrrolidin-1-ylmethyl)phenylamino)-6- cyanobenzo[d]thiazole





356


embedded image


506
(R)-2-(benzo[d]thiazol-2-ylamino)-4-(3- hydroxypropylamino)-6-(pyrrolidin-3- ylamino)-1,3,5-triazine





357


embedded image


507
(R)-2-(benzo[d]thiazol-2-ylamino)-4-(2- hydroxyethylamino)-6-(pyrrolidin-3- ylamino)-1,3,5-triazine





358


embedded image


508
(R)-2-(benzo[d]thiazol-2-ylamino)-4- methylamino-6-(pyrrolidin-3-ylamino)-1,3,5- triazine





359


embedded image


509
2-((6-fluorobenzo[d]thiazol-2-yl)amino)-N- (pyrrolidin-3-yl)isonicotinamide





360


embedded image


510
2-((6-hydroxybenzo[d]thiazol-2-yl)amino)-N- (pyrrolidin-3-yl)isonicotinamide





361


embedded image


511
2-((6-trifluoromethylbenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide





362


embedded image


512
2-((6-trifluoromethoxybenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide





363


embedded image


513
2-((6-methoxybenzo[d]thiazol-2-yl)amino)-6- methyl-N-(pyrrolidin-3-yl)isonicotinamide





364


embedded image


514
2-((6-hydroxymethylbenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide





365


embedded image


515
(R)-2-((6-methoxybenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide





366


embedded image


516
(S)-2-((6-phenylbenzo[d]thiazol-2-yl)amino)- N-(pyrrolidin-3-yl)isonicotinamide





367


embedded image


517
(S)-2-((6-methylsulfonylbenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide





368


embedded image


518
2-((quinolin-2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide





369


embedded image


519
(S)-2-((6-cyanoquinolin-2-yl)amino)-N- (pyrrolidin-3-yl)isonicotinamide





370


embedded image


520
(R)-2-((6-N-methyl-N-(2- methoxyethyl)benzo[d]thiazol-2-yl)amino)- N-(pyrrolidin-3-yl)isonicotinamide





371


embedded image


521
(R)-2-((6-morpholinobenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide





372


embedded image


522
2-((6-(1H-pyrazol-4-yl)benzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)-4- pyrimidinecarboxamide





373


embedded image


523
5-((6-(1H-pyrazol-4-yl)benzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)nicotinamide





374


embedded image


524
2-((6-bromobenzo[d]thiazol-2-yl)amino)-4- (N-methyl-N-(2- methoxyethyl)aminomethyl)pyridine





375


embedded image


525
2-((6-bromobenzo[d]thiazol-2-yl)amino)-4- (morpholinomethyl)pyridine





376


embedded image


526
2-((6-bromobenzo[d]thiazol-2-yl)amino)-4- (4-methylpiperazinomethyl)pyridine





377


embedded image


527
2-((6-(3,5-dimethylisoxazol-4- yl)benzo[d]thiazol-2-yl)amino)-4-(pyrrolidin- 1-ylmethyl)pyridine





378


embedded image


528
2-((6-(3-chloropyridin-4-yl)benzo[d]thiazol-2- yl)amino)-4-(pyrrolidin-1-ylmethyl)pyridine





379


embedded image


529
2-((6-(3-methoxyphenyl)benzo[d]thiazol-2- yl)amino)-4-(pyrrolidin-1-ylmethyl)pyridine





380


embedded image


530
2-((6-(3,5-dimethylpyrazol-4- yl)benzo[d]thiazol-2-yl)amino)-4-(pyrrolidin- 1-ylmethyl)pyridine





381


embedded image


531
2-((6-(2,2,2-trifluoroethyl)benzo[d]thiazol-2- yl)amino)-4-(pyrrolidin-1-ylmethyl)pyridine





382


embedded image


532
2-((6-(2,2,2-trifluoroethyl)benzo[d]thiazol-2- yl)amino)-4-(4-methoxyacetylpiperazin-1- yl)pyridine





383


embedded image


533
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (1-cyanoacetylpiperidin-4-yl)pyridine





384


embedded image


534
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (1-cyanomethylpiperidin-4-yl)pyridine





385


embedded image


535
2-((6-(imidazol-1-yl)benzo[d]thiazol-2- yl)amino)-4-hydroxymethylpyridine





386


embedded image


536
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (1-(4-methoxyphenyl)acetylpiperidin-4- yl)pyridine





387


embedded image


537
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (1-(3-cyclopentyl-1-oxopropyl)piperidin-4- yl)pyridine





388


embedded image


538
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (1-(1-oxopropyl)piperidin-4-yl)pyridine





389


embedded image


539
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (1-cyclopropylcarbonylpiperidin-4- yl)pyridine





390


embedded image


540
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (1-trifluoroacetylpiperidin-4-yl)pyridine





391


embedded image


541
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (1-ethylsulfonylpiperidin-4-yl)pyridine





392


embedded image


542
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (1-methoxyacetylpiperidin-4-yl)pyridine





393


embedded image


543
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (piperidin-4-yl)pyridine





394


embedded image


544
2-((6-(pyrazol-1-yl)benzo[d]thiazol-2- yl)amino)-4-(pyrrolidin-1-ylmethyl)pyridine





395


embedded image


545
2-((6-(3-fluoropyridin-4-yl)benzo[d]thiazol-2- yl)amino)-4-(pyrrolidin-1-ylmethyl)pyridine





396


embedded image


546
2-((6-(pyrazol-4-yl)benzo[d]thiazol-2- yl)amino)-4-hydroxymethyl-3-fluoropyridine





397


embedded image


547
2-((6-bromobenzo[d]thiazol-2-yl)amino)-4- hydroxymethylpyridine





398


embedded image


548
2-((6-bromobenzo[d]thiazol-2-yl)amino)-4- ethylpyridine





399


embedded image


549
5-((6-cyanobenzo[d]thiazol-2-yl)amino)-3- methylisoxazole





400


embedded image


550
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-5- methyl-4-phenylthiazole





401


embedded image


551
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-5- (4-methoxyphenyl)-1,3,4-thiadiazol





402


embedded image


552
2-((6-(oxazol-5-yl)benzo[d]thiazol-2- yl)amino)-4-(4-(2-methoxyethyl)piperazin-1- yl)pyridine





403


embedded image


553
2-((6-(2-methyl-1,3,4-oxadiazol-5- yl)benzo[d]thiazol-2-yl)amino)-4- ethylpyridine





404


embedded image


554
2-(3-hydroxymethylphenyl)amino-6- cyanobenzo[d]thiazole





405


embedded image


555
2-((6-(1,3,4-oxadiazol-2-yl)benzo[d]thiazol- 2-yl)amino)-4-ethylpyridine





406


embedded image


556
2-((6-(1,3,4-thiadiazol-2-yl)benzo[d]thiazol- 2-yl)amino)-4-ethylpyridine





407


embedded image


557
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (pyrrolidin-1-ylmethyl)pyridine





408


embedded image


558
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (pyrrolidin-1-ylthiocarbonyl)pyridine





409


embedded image


559
2-(3,5-dimethoxymethylphenyl)amino-6- cyanobenzo[d]thiazole





410


embedded image


560
4-((6-(1H-pyrazol-4-yl)benzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)-6- pyrimidinecarboxamide





411


embedded image


561
5-(5-methyl-1H-pyrazol-4-yl)-2-(4- hydroxymethylpyridin-2- ylamino)thiazolo[5,4-b]pyridine





412


embedded image


562
5-(pyridin-4-yl)-2-(5- isopropyloxymethylisoxazol-3- ylamino)thiazolo[5,4-b]pyridine





413


embedded image


563
5-(1H-pyrazol-4-yl)-2-(3-(4- methoxyacetylpiperazin-1- ylphenyl)amino)thiazolo[5,4-b]pyridine





414


embedded image


564
5-ethyl-2-(3-(4-methoxyacetylpiperazin-1- ylphenyl)amino)thiazolo[5,4-b]pyridine





415


embedded image


565
5-ethyl-2-(4-(1-methoxyacetylpiperidin-4- ylpyridin-2-yl)amino)thiazolo[5,4-b]pyridine





416


embedded image


566
5-ethyl-2-(4-(pyrrolidon-1-ylpyridin-2- yl)amino)thiazolo[5,4-b]pyridine





417


embedded image


567
5-(pyridine-4-yl)-2-(4-(3-dimethylamino-3- oxopropyl)pyridin-2-yl)amino)thiazolo[5,4- b]pyridine





418


embedded image


568
5-(1-methylimidazol-5-yl)-2-(4-(4- methoxyacetylpiperazin-1-ylpyridin-2- yl)amino)thiazolo[5,4-b]pyridine





419


embedded image


569
5-(pyrimidin-4-yl)-2-(4-(4- methoxyacetylpiperazin-1-ylpyridin-2- yl)amino)thiazolo[5,4-b]pyridine





420


embedded image


570
5-(thiazol-5-yl)-2-(4-(4- methoxyacetylpiperazin-1-ylpyridin-2- yl)amino)thiazolo[5,4-b]pyridine





421


embedded image


571
5-propyl-2-(4-(4-methoxyacetylpiperazin-1- ylpyridin-2-yl)amino)thiazolo[5,4-b]pyridine





422


embedded image


572
5-(1H-pyrazol-4-yl)-2-(2-pyrrolidon-1- ylmethylpyridin-4-yl)amino)thiazolo[5,4- b]pyridine





423


embedded image


573
5-(pyridin-4-yl)-2-(4-(1-methyl-2- oxopiperidin-4-ylpyridin-2- yl)amino)thiazolo[5,4-b]pyridine





424


embedded image


574
5-(1-methylimidazol-5-yl)-2-(4-(2- dimethylaminocarbonylethyl)pyridin-2- yl)amino)thiazolo[5,4-b]pyridine





425


embedded image


575
5-(pyridine-4-yl)-2-(4-(4- methoxyacetylpiperazin-1-ylpyridin-2- yl)amino)oxazolo[5,4-b]pyridine





426


embedded image


576
2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (1-phenylcarbonylpiperidin-4-yl)pyridine





427


embedded image


577
6-cyano-2-(4-(4-methoxyacetyl-piperazin-1- yl)pyridin-2-ylamino)imidazo[1,2-a]pyridine





428


embedded image


578
6-cyano-2-(4-(4-(2-methoxyethyl)piperazin- 1-yl)pyridin-2-ylamino)imidazo[1,2- a]pyridine





429


embedded image


579
6-(1H-pyrazol-4-yl)-2-(4-morpholinopyridin- 2-ylamino)imidazo[1,2-a]pyridine





430


embedded image


580
5-(pyridin-3-yl)-2-(4-(piperazin-1- ylmethylpyridin-2-yl)amino)thiazolo[5,4- b]pyridine









Example 431
Inhibition Assay

The following assay is useful for evaluating test compounds for inhibition of IRAK-1 or IRAK-4 kinase activity. A 96-well polystyrene microtiter plates are coated with neutravidin for IRAK-1 or streptavidin for IRAK-4 (10 mg/mL in PBS, overnight at 4° C.). The coating solution is removed and in 80 μL/well, a kinase reaction mixture is added (for IRAK-1: mM Tris-HCl, pH 7.5, 10 mM MgCl2, 2 mM EGTA, 1 mM NaF, 0.5 mM benzamidine, 1 mM DTT, 3 μM ATP, 1 mM of biotinylated substrate peptide bio-ARFSRFAGSSPSQSSMVAR, sequence derived from IRAK-1; for IRAK-4: 20 mM Tris-HCl, pH 7.5, 10 mM MgCl2, 2 mM EGTA, 1 mM NaF, 0.5 mM benzamidine, 1 mM DTT, 10% glycerol, 10 μM ATP, 1 mM of biotinylated substrate peptide bio-RRRVTSPARRS, sequence derived from GFAP).


At 10 μL/well in DMSO test compounds are added covering a final concentration range from 1 nM to 30 mM. Recombinant, full-length IRAK-1 or IRAK-4 enzyme (baculovirus expression system) is added in 10 μL buffer containing 20 mM Tris-HCl, pH 7.5, 2 mM EGTA, 0.5 mM benzamidine, 1 mM DTT, 10 mM MgCl2, and glycerol 10% (IRAK-4 only) to initiate the kinase reaction. The reaction mixture is incubated at room temperature for 60 min on a shaker. During this incubation the substrate peptide is being phosphorylated by the kinase and gets captured onto the surface of the wells by neutravidin or streptavidin, respectively. The plate is washed 3× with 150 μL distilled water to terminate the reaction and remove components of the reaction mixture. A conventional chemiluminescent ELISA detection technique is initiated by adding 100 μL/well primary antibody (monoclonal antibody YC10, generated to recognize the phosphorylated epitope in the substrate peptide; use at 1:20,000 dilution for IRAK-1 and 1:10,000 dilution for IRAK-4) premixed with horseradish peroxidase (HRP) conjugated anti-mouse secondary antibody (commercially available from several sources; use at 1:10,000 dilution) in PBS containing 2% BSA. The solution is incubated at room temperature for 40 min on a shaker, then washed 3× with 150 μL of water. 100 μL 10× diluted SuperSignal HRP substrate (from Pierce) is added and after 5 min incubation the chemiluminescent signal is captured by a Labsystems LuminoSkan luminometer. The point of 50% inhibition of IRAK-1 or IRAK-4 enzyme activity (IC50) is determined. Table 4 summarizes data obtained using an assay substantially similar to the foregoing method (Compound: Cmpd).
















TABLE 4





Cmpd
EC50
Cmpd
EC50
Cmpd
EC50
Cmpd
EC50







101
A
110
A
120
A
130
A


137
A
150
A
160
A
170
A


180
A
190
A
200
A
210
A


220
A
230
A
240
A
250
A


260
A
270
A
280
A
290
A


300
A
310
A
320
A
330
A


340
A
350
A
360
A
370
A


380
A
390
A
401
A
410
A


420
A
430
A
439
A
484
B


490
A
500
A
510
B
521
B


530
B
540
A
553
B
560
B


570
A
580
B









It is to be understood that both the foregoing general description and detailed description are exemplary and explanatory only and are not restrictive of the embodiments claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of “or” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “includes,” and “included,” is not limiting. The term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.


All references cited herein, including but not limited to published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and are hereby made a part of this specification. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.


All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.


The above description discloses several methods and materials of the present invention. This invention is susceptible to modifications in the methods and materials, as well as alterations in the fabrication methods and equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure or practice of the invention disclosed herein. Consequently, it is not intended that this invention be limited to the specific embodiments disclosed herein, but that it cover all modifications and alternatives coming within the true scope and spirit of the invention.

Claims
  • 1. A compound of Formula (I-A):
  • 2. The compound of claim 1, wherein R4 is pyrazolyl substituted with methyl.
  • 3. The compound of claim 1, wherein R4 is pyrazolyl.
  • 4. The compound of claim 1 selected from the group consisting of:
  • 5. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
  • 6. The compound of claim 1, wherein R1 is C1-C6 alkyl substituted with pyrrolidinyl.
  • 7. The compound of claim 1, wherein R1 is C1-C6 alkyl substituted with pyrrolidinyl substituted with methyl.
  • 8. The compound of claim 1, wherein R1 is C1-C6 alkyl substituted with pyrrolidinyl substituted with methoxy.
  • 9. The compound of claim 1, having the structure:
RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 13/885,138 filed May 13, 2013 which is the U.S. National Phase of Application No. PCT/US2011/061532 entitled “HETEROCYCLE AMINES AND USES THEREOF” filed Nov. 18, 2011 and published in English on May 24, 2012 as WO2012/068546 which claims the benefit of U.S. Provisional Application No. 61/415,685 filed Nov. 19, 2010 entitled “HETEROCYCLE AMINES AND USES THEREOF” which is incorporated herein by reference in its entirety.

US Referenced Citations (1)
Number Name Date Kind
20070066577 Choo et al. Mar 2007 A1
Foreign Referenced Citations (22)
Number Date Country
1674466 Jun 2006 EP
2277881 Jan 2011 EP
S48-78166 Oct 1973 JP
2000-086641 Mar 2000 JP
2006-520805 Sep 2006 JP
2007-518765 Jul 2007 JP
2008-255024 Oct 2008 JP
2009-523803 Jun 2009 JP
2009-524670 Jul 2009 JP
WO9924035 May 1999 WO
WO 03082272 Oct 2003 WO
WO 2005037285 Apr 2005 WO
WO2007016392 Feb 2007 WO
WO 2008030579 Mar 2008 WO
WO 2008030584 Mar 2008 WO
WO2009126635 Oct 2009 WO
WO 2009128520 Oct 2009 WO
WO 2010057121 May 2010 WO
WO 2010106016 Sep 2010 WO
WO 2010135014 Nov 2010 WO
WO 2010144909 Dec 2010 WO
2011110575 Sep 2011 WO
Non-Patent Literature Citations (11)
Entry
Jordan “Tamoxifen . . . .” Nature Rev. v.2, p. 205-213 (2003).
Ettmayer et al. “Lessons Learned from Marketed and Investigational Prodrugs.” J. Med. Chem., (2004), 47(10): 2393-2404.
Stella, Valentino. “Prodrugs as therapeutics.” Expert Opin. Ther. Patents (2004), 14(3): 277-280.
Testa, Bernard. “Prodrug research: futile or fertile?” Biochemical Pharmacology, 68 (2004): 2097-2106.
Balant ed in Wolff et al. Burger's Medicinal Chemistry and Drug Discovery. 5th ed. vol. 1: Principles and Practice. pp. 949-982, 1996.
Dorwald , Side Reactions in Organic Synthesis, 2005, Wiley: VCH Weinheim Preface, pp. 1-15 & Chapter 8, pp. 279-308.
Das, J.; et al. Discovery of 2-amino-heteroaryl-benzothiazole-6-anilides as potent p56lck inhibitors., Bioorg Med Chem Lett. Aug. 4, 2003;13(15):2587-90.
Caleta et al., “Novel Cyano- and Amidinobenzothiazole Derivatives: Synthesis, Antitumor Evaluation, and X-ray and Quantitative Structure—Activity Relationship (QSAR) Analysis”, J. Med. Chem. 2009, 52, 1744-1756.
International Search Report dated May 16, 2012 received in International Application No. PCT/US2011/061532.
Greene, et al., “Protective Groups in Organic Synthesis” 3rd Ed., John Wiley & Sons, New York, NY, 1999.
Yin, J. et al, “Pd-Catalyzed N-Arylation of Heteroarylamines,”Org. Lett. 4:3481-3484 (2002).
Related Publications (1)
Number Date Country
20140155379 A1 Jun 2014 US
Provisional Applications (1)
Number Date Country
61415685 Nov 2010 US
Continuations (1)
Number Date Country
Parent 13885138 US
Child 14137318 US