Heteroaromatic compounds, pharmaceutical compositions thereof, and uses thereof

Abstract

The present invention provides a new class of aromatic heterocyclic compounds as ATX (Autotaxin) inhibitors, pharmaceutical compositions comprising the compounds, and the use of the compounds and compositions in the treatment of diseases in mammals having a pathological characteristic of increased expression of ATX (Autotaxin), wherein the compounds have the structure of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitroso, metabolite, prodrug, or mixture thereof; wherein, R 1 , Ar 1 , Ar 2 , Ar 3 , W, Y, Z and Cy have the definitions described in the present invention.

Description

Field of the invention

[0001] The present invention relates to the field of medicinal chemistry, in particular to a new class of aromatic heterocyclic compounds as ATX (Autotaxin) inhibitors, to pharmaceutical compositions comprising said compounds, and to the use of said compounds or compositions in the treatment of diseases having as pathological feature an increased expression of ATX (Autotaxin). BACKGROUND

[0002] Autotaxin (ATX) was first isolated from A2058 melanoma cells in 1992 and was named "autocrine motility factor" as a secreted glycoprotein. ATX has phosphodiesterase (PDE) activity and is a member of the ecto-nucleotide pyrophosphatase / phosphodiesterase (ENPP) family. ATX also has lysophospholipase D (lysoPLD) activity and can catalyze lysophosphatidylcholine (LPC) to generate lysophosphatidic acid (LPA). LPA is not only a precursor of phospholipids, but also can cause a wide range of biological effects through various signal transduction pathways. Once generated, LPA can mediate the action through six cell surface-specific receptor proteins (LPA1-6), namely G protein-coupled receptors (GPCRs). According to the endothelial cell differentiation gene (Edg) and ventricular zone gene nomenclature, LPA1-6 are LPA1 / Edg-2 / VZG-1, LPA2 / Edg-4, LPA3 / Edg-7, LPA4 / p2y9 / GPR23, LPA5 / GPR92 and LPA6 / p2Y5, respectively. Each receptor is mediated by Gα protein (Gs, Gi, Gq, and G12 / 13), and then a series of cell signal cascades are triggered. Among them, the main pathways include the hydrolysis of phosphatidylinositol bisphosphate (PIP2), which in turn triggers intracellular calcium ion release and protein kinase C (PKC) activation; inhibition of adenosine cyclase (cAMP) signaling pathway; activation of Ras-MAPK, MERK, ERK pathway to regulate cell proliferation activity; activation of phosphoinositide PI3K-AKT pathway to regulate cell survival and apoptosis activity; finally, activation of Rho pathway to regulate cytoskeleton remodeling, shape change and cell migration activity. In many pathological conditions, especially in tumor cells, ATX is in a high expression state, leading to excessive LPA concentration. In tumor cells, LPA concentration can be increased to 10 μmol / L, which is much higher than the normal level of 100 nmol / L. Excessive LPA increases the generation of vascular endothelial growth factor (VEGF) and promotes angiogenesis; reduces the expression of tumor suppressor p53, and increases the survival and metastasis of tumor cells. The ATX-LPA signaling pathway is involved in many physiological and pathological processes, and is therefore closely related to many serious diseases, mainly including cardiovascular diseases, autoimmune diseases, cancer, fibrosis diseases, inflammation, nervous system diseases, pain, etc. LPA has multiple functions in tumor generation, promoting tumor cell growth, angiogenesis, metastasis and drug resistance. Therefore, reducing the concentration level of LPA is beneficial to the treatment and control of tumors. Correspondingly, inhibiting the activity of AXT and blocking the generation pathway of LPA are research hotspots for the treatment of various serious diseases.

[0003] With the deepening of the research on ATX, many new inhibitors targeting ATX have emerged, among which the most concentrated researches are cancer and fibrosis diseases. Fibrosis diseases mainly include idiopathic pulmonary fibrosis (IPF) and liver fibrosis. IPF is a fatal disease characterized by diffuse alveolar inflammation and alveolar structure disorder, which leads to the progressive development of pulmonary interstitial fibrosis. The prognosis is poor, and the average survival time is 2 to 5 years. IPF is the disease most closely related to the ATX-LPA pathway, because the expression of ATX in lung tissue is highest in bronchial epithelial cells and alveolar macrophages, which can be juxtaposed into fibrocytic foci.

[0004] At present, GLPG-1690, as an autotaxin inhibitor, has entered the clinical phase II trial for the treatment of idiopathic pulmonary fibrosis; the concentration of ATX in serum is closely related to liver fibrosis and liver stiffness value, and is one of the best indicators for predicting cirrhosis. In addition, ATX is highly expressed in many tumor tissues, including melanoma, non-small cell lung cancer, liver cancer, kidney cancer, breast cancer, thyroid cancer, ovarian cancer and Hodgkin's lymphoma. LPA / ATX can promote cell invasion and metastasis during tumor cell growth. Therefore, ATX inhibitors, which block the signal transduction pathway, provide a new way for the clinical treatment of cancer and fibrosis diseases.

[0005] Compared with traditional kinase inhibitors, ATX inhibitors can inhibit ATX activity while affecting multiple signal pathways related to cell proliferation, growth and apoptosis, and have better inhibitory effect on some drug-resistant tumors, and are closely related to fibrosis of multiple organs, and are important targets for the research and development of new fibrosis disease drugs.

[0006] The present application provides a new class of aromatic heterocyclic compounds, which have good inhibitory activity on ATX. The compounds of the present application have excellent pharmacodynamic, pharmacokinetic and / or toxicological properties, and have better clinical application prospects. ABSTRACT

[0007] The following only outlines some aspects of the present application, but is not limited thereto. These aspects and other parts will be more fully described later. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of this specification and the cited references differ, the disclosure of this specification shall prevail.

[0008] The present application provides a new class of compounds that effectively inhibit ATX activity, which can be used to prepare a medicament for treating a disease having an increased expression of ATX as a pathological feature, such as cancer, fibrotic diseases (e.g. idiopathic pulmonary fibrosis or liver fibrosis), metabolic diseases, myelodysplastic syndromes, cardiovascular diseases, autoimmune diseases, inflammation, nervous system diseases or pain. The present application also provides a method for preparing the compounds described herein, a method for using these compounds to treat the above-mentioned diseases in mammals, especially humans, and a pharmaceutical composition comprising these compounds.

[0009] In one aspect, the present application provides a new class of aromatic heterocyclic compounds, which are represented by Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitroso, metabolite, prodrug, or mixture of the compound represented by Formula (I):

[0010]

[0011] wherein,

[0012] W is -N(R 1a )-, -O-, -S-, -S(=O) 1-2 -, -C(=O)-, -(C(R 2a )(R 2b )) 1-4 -, -N(R 1a )(C(R 2a )(R 2b )) 1-4 -, -N(R 1a )C(=O)-, or -O(C(R 2a )(R 2b )) 1-4 -;

[0013] Ar 1 and Ar 2 are each independently a five-membered heteroaryl group, wherein Ar 1 and Ar 2 are independently optionally substituted with 1, 2, or 3 R 2 ;

[0014] Ar 3 is an aryl group, or a heteroaryl group, wherein the Ar 3 is independently optionally substituted with 1, 2, 3, or 4 R 3 ;

[0015] Cy is a cycloalkyl group, a heterocyclyl group, a spirobicyclic group, a spiroheterobicyclic group, a fused bicyclic group, a fused heterobicyclic group, a bridged cyclic group, a bridged heterocyclic group, an aryl group, or a heteroaryl group, wherein the Cy is optionally substituted with 1, 2, 3, or 4 R 4 ;

[0016] Y is -(L 1 -W 1 ) m -L 2 -;

[0017] L 1 is absent, or L 1 is -O-, -C(=O)-, -N(R i )-, -N(R h )C(=O)-, or -S(=O) 0-2 -;

[0018] W 1 is C 1-4 alkylene, said C 1-4 alkylene being optionally substituted with 1, 2, 3, or 4 groups independently selected from H, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, and C 1-6 alkoxy;

[0019] L 2 is absent, or L 2 is -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)-C(=O)-, -C(=O)-C(=O)N(R a )-, -N(R b )-, -C(=O)N(R c )-, -N(R c )C(=O)-, -C(=O)N(R c )-R 15 -C(=O)O-, -C(=O)N(R c )-R 15 -C(=O)N(R a )-, -N(R d )C(=O)N(R c )-, -N(R g )C(=O)O-, -S(=O) 0-2 -, -S(=O) 1-2 N(R e )-, -N(R f )S(=O) 1-2 -, or -N(R f )S(=O) 1-2 -R 15 -N(R a )-;

[0020] Z is H, -CN, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, heterocyclic alkyl, cycloalkylalkyl, spirobicyclo, spiroheterocyclic, fused bicyclo, fused heterobicyclo, bridged cycloalkyl, bridged heterocyclic, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, spirobicyclo, spiroheterocyclic, fused bicyclo, fused heterobicyclo, bridged cycloalkyl, bridged heterocyclic, aryl, or heteroaryl is optionally surrounded by one or more R. 5 replace;

[0021] R 1 It is an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic group, wherein R 1 Independently and optionally by 1, 2, 3 or 4 R 6 replace;

[0022] Each R 2 Each of the following can be independently represented as H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkoxyalkyl, aryloxyalkyl, -S (=O). 0-2 R 7 -C(=O)R 8 -OS (=O) 1-2 R 7a -OC(=O)R 8a -C(=O)OR 8a -N(R) 9a )C(=O)R 9 -OC(=O)NR 10 R 10a -NR 11 R 11a -N(R) 12 S(=O) 1-2 R 12a -N(R) 13 )C(=O)NR 13a R 13b -R 14 -S(=O) 0-2 R 7 -R 14 -C(=O)R 8 -R 14 -OS(=O) 1-2 R 7a -R 14 -OC(=O)R 8a -R 14 -N(R 9a )C(=O)R 9 -R 14-OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b ;

[0023] R 2a and R 2b are each independently H, -CN, -OH, -NH2, F, Cl, Br, I, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, aryl, aralkyl, heteroaryl, or heteroarylalkyl;

[0024] each R 3 is independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R9a )C(=O)R 9 -R 14 -OC(=O)NR 10 R 10a -R 14 -NR 11 R 11a -R 14 -N(R 12 S(=O) 1-2 R 12a or -R 14 -N(R 13 )C(=O)NR 13a R 13b ;

[0025] Each R 4 The following can be independently represented as H, oxo (C=O), -CN, -NO2, -OH, -NH2, F, Cl, Br, I, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, and -S (=O). 0-2 R 7 -C(=O)R 8 -OS (=O) 1-2 R 7a -C(=O)OR 8a -OC(=O)R 8a -N(R) 9a )C(=O)R 9 -C(=O)NR 9a R 9 -OC(=O)NR 10 R 10a -NR 11 R 11a -N(R) 12 S(=O) 1-2 R 12a -N(R) 13 )C(=O)NR 13a R 13b -R 14 -S(=O) 0-2 R 7 -R 14 -C(=O)R 8 -R 14 -OS(=O) 1-2 R 7a -R 14 -OC(=O)R 8a -R 14 -N(R 9a )C(=O)R 9 -R 14-OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b ;

[0026] each R 5 is independently H, oxo (C=O), -CN, -NO2, -OH, -NH2, F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkylamino, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, aryl, aralkyl, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b ;

[0027] each R 6 is independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14-N(R 13 )C(=O)NR 13a R 13b ;

[0028] each R 7 , R 7a , R 8 , R 8a , R 9 , and R 12a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, cyano-substituted C 1-6 alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl;

[0029] each R 9a , R 10 , and R 10a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano-substituted C 1-6 alkyl, or haloC 1-6 alkyl;

[0030] each R 11 and R 11a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, cyano-substituted C 1-6 alkyl, or aralkyl;

[0031] each R 12 , R 13 , R 13a , and R 13b is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano-substituted C 1-6 alkyl, or haloC 1-6 alkyl;

[0032] R 1a is independently H, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;

[0033] each R a , R b , R c , Rd e f g h i each R is independently H, alkyl, alkenyl, alkynyl, cyano-substituted alkyl, haloalkyl, R 16 -C(=O)-, or cycloalkylalkyl;

[0034] each R 14 15 each R is independently alkylene, alkenylene, alkynylene, cyano-substituted alkylene, or haloalkylene;

[0035] R 16 is H, C 1-6 alkyl or haloC 1-6 alkyl; and

[0036] m is 0, 1 or 2.

[0037] In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present application or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitroxide, metabolite, prodrug, and pharmaceutically acceptable excipient, diluent or carrier thereof.

[0038] In some embodiments, the pharmaceutical composition of the present application further comprises an additional therapeutic agent.

[0039] In another aspect, the present application provides use of a compound of the present application or a pharmaceutical composition of the present application in the manufacture of a medicament for preventing or treating a disease having an increased expression of ATX as a pathological characteristic in a mammal.

[0040] In some embodiments, the disease having an increased expression of ATX as a pathological characteristic comprises cancer, fibrotic disease, metabolic disease, myelodysplastic syndrome, cardiovascular disease, autoimmune disease, inflammation, nervous system disease, or pain.

[0041] In some embodiments, the disease having an increased expression of ATX as a pathological characteristic is idiopathic pulmonary fibrosis or liver fibrosis. DETAILED DESCRIPTION

[0043] DEFINITIONS AND GENERAL TERMINOLOGY

[0044] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications referred to in this application are incorporated herein by reference in their entirety.

[0045] ​​​​​​Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the terms used in the present disclosure. For purposes of the present disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the "Handbook of Chemistry and Physics" 75thEd. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0046] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to "at least one") of the grammatical object of the article. By way of example, "a component" means one or more components, and thus, possibly, more than one component is contemplated and can be employed or used in practicing the embodiments of the present disclosure.

[0047] The term "mammal" as used herein refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, pigs, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the mammal is a primate. In other embodiments, the mammal is a human.

[0048] The term "patient" as used herein refers to either a human (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

[0049] The term "comprising" is a broad term of art used to encompass the elements following that term. It will be understood by those skilled in the art that "comprising" can also mean "consisting essentially of' or "consisting of."

[0050] "Stereoisomers" refer to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans), atropisomers, and the like.

[0051] "Chiral" refers to a molecule which has the property of non-superimposability on its mirror image; while "achiral" refers to a molecule which is superimposable on its mirror image.

[0052] "Enantiomers" refer to two isomers of a compound which are not superimposable on their mirror image.

[0053] "Diastereomers" refers to two or more stereoisomers of a compound which are not mirror images of one another and which have different physical properties. Mixtures of diastereomers can be separated by methods well known in the art such as, for example, high resolution analysis operations such as electrophoresis and chromatography, e.g., HPLC.

[0054] The stereochemical definitions and rules used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0055] Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound; (-) or 1 meaning that the compound is levorotatory. A compound, which is (+) or d is dextrorotatory. A particular stereoisomer is the enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, and this occurs where there has been no stereocontrol in a chemical reaction or process.

[0056] Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in the racemic or enantiomeric enriched form, e.g., the (R)-, (S)-, or (R,S)-configurational form. In certain embodiments, each asymmetric atom is in at least a 50% enantiomeric excess of the (R)- or (S)- configuration, at least a 60% enantiomeric excess, at least a 70% enantiomeric excess, at least an 80% enantiomeric excess, at least a 90% enantiomeric excess, at least a 95% enantiomeric excess, or at least a 99% enantiomeric excess.

[0057] Depending on the starting materials and the choice of the method, the compounds of the present application can exist in one of the possible isomers or mixtures thereof, for example, as racemates and as mixtures of diastereoisomers, depending on the number of asymmetric carbon atoms. The optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or by resolution of the racemates using conventional techniques. If the compounds contain a double bond, the substituents can be in the E or Z configuration; if the compounds contain a disubstituted cycloalkyl, the substituents on the cycloalkyl can be in the cis or trans configuration.

[0058] Any mixture of stereoisomers resulting can be separated into the individual isomers by conventional techniques, or can be used directly in accordance with the application. The resulting pure or substantially pure geometric isomers, optical isomers, diastereoisomers may, for example, be separated by chromatography and / or fractional crystallization.

[0059] Any racemate of an end product or intermediate can be separated by the techniques of the art into the individual optical antipodes, for example, by the formation of a salt with a non-racemic isomer of the compound. The racemate can also be separated by the use of chiral chromatography, for example, high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, the antipodes can be prepared by asymmetric synthesis, for example, as described in Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0060] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridin-4-ol and pyridin-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention. "Pharmaceutically acceptable" means compounds, raw materials, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems and complications commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0061] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or as specific examples, subclasses, and a class of compounds included in this invention, as described in the embodiments / schemes.

[0062] Generally, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, a substituted group may have one substituent at each substituted position of the group. When more than one position in a given structural formula can be replaced by one or more substituents selected from a specific group, the substituents may be substituted at each position in the same or different manner.

[0063] The term "unsubstituted" means that the specified group does not have substituents.

[0064] The term "optionally substituted by..." can be used interchangeably with the term "unsubstituted or substituted by...", meaning that the structure is unsubstituted or substituted by one or more substituents as described in this invention, including, but not limited to, D, F, Cl, Br, I, N3, CN, NO2, OH, SH, NH2, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -S (=O).0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -C(=O)NR 9a R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , -R 14 -N(R 13 )C(=O)NR 13a R 13b and the like, wherein R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , R 10a , R 11 , R 11a , R 12 , R12a R 13 R 13a R 13b and R 14 have the meanings given in the present invention.

[0065] Further, it should be noted that the description "each independently" used in the present invention is interchangeable with "each independently" and "independently" unless explicitly indicated otherwise, and should be interpreted broadly, which means that the specific options expressed by the same symbol among different groups do not affect each other, and the specific options expressed by the same symbol among the same group do not affect each other.

[0066] In various portions of the specification, substituents of the compounds disclosed herein are disclosed by group or range. It is specifically intended that the present invention include each and every independent combination of the members of these groups and ranges. For example, the term "C1-C6alkyl" specifically includes each and every individual alkyl sub-group within the C1-C6range, i.e. C1, C2, C3, C4, C5, and C6. 1-6 "alkyl" specifically includes the individual disclosure of methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl.

[0067] In various portions of the specification, connecting substituents are described. When the structure clearly requires a connecting group, the Markush variable recited for that group should be interpreted as a connecting group. For example, if the structure requires a connecting group and the Markush group definition recited for that variable recites "alkyl" or "aryl", then it should be understood that the "alkyl" or "aryl" represents a connected alkylene group or arylene group, respectively.

[0068] The term "alkyl" or "alkyl group" as used herein means a straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group can be optionally substituted with one or more substituents as described herein. Unless otherwise specifically indicated, an alkyl group contains 1-20 carbon atoms. In one embodiment, an alkyl group contains 1-12 carbon atoms; in another embodiment, an alkyl group contains 1-6 carbon atoms; in yet another embodiment, an alkyl group contains 1-4 carbon atoms; and in still another embodiment, an alkyl group contains 1-3 carbon atoms. The alkyl group can be optionally substituted with one or more substituents as described herein.

[0069] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), i-propyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), i-butyl (i-Bu, -CH2CH(CH3)2), s-butyl (s-Bu, -CH(CH3)CH2CH3), t-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0070] The term "alkylene" denotes a saturated divalent hydrocarbyl radical resulting from the removal of two hydrogen atoms from a saturated straight chain or branched chain hydrocarbon radical. Unless otherwise specifically indicated, an alkylene group contains 1 to 12 carbon atoms. In one embodiment, an alkylene group contains 1 to 6 carbon atoms; in another embodiment, an alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, an alkylene group contains 1 to 3 carbon atoms; and in still another embodiment, an alkylene group contains 1 to 2 carbon atoms. Examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like. The alkylene group can be optionally substituted with one or more substituents described herein.

[0071] The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon group containing from 2 to 12 carbon atoms, wherein there is at least one site of 2 double bond, including "cis" and "trans" eonfigurations, or "E" and "Z" configurations. In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), and the like. The alkenyl group can be optionally substituted with one or more substituents described herein.

[0072] The term "alkenylene" denotes a straight or branched chain divalent hydrocarbon group containing from 2 to 12 carbon atoms, wherein there is at least one site of 2 double bond, including "cis" and "trans" eonfigurations, or "E" and "Z" configurations. Unless otherwise specified, the alkenylene group contains 2 to 12 carbon atoms. In one embodiment, the alkenylene group contains 2 to 6 carbon atoms; in another embodiment, the alkenylene group contains 2 to 4 carbon atoms; in yet another embodiment, the alkenylene group contains 2 to 3 carbon atoms; and in still another embodiment, the alkenylene group contains 2 carbon atoms. Examples of such include vinylenyl (-CH=CH-), allylenyl (-CH2CH=CH-), and the like. The alkenylene group can be optionally substituted with one or more substituents described herein.

[0073] The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon group containing from 2 to 12 carbon atoms, wherein there is at least one site of

[0074] The term "alkynylene" denotes a straight-chained or branched bivalent hydrocarbon group containing 2 to 12 carbon atoms, wherein at least one unsaturation, i.e., one carbon-carbon sp3 bond, is present. In one embodiment, the alkynylene group contains 2 to 8 carbon atoms; in another embodiment, the alkynylene group contains 2 to 6 carbon atoms; in yet another embodiment, the alkynylene group contains 2 to 4 carbon atoms. Examples of alkynylene groups include, but are not limited to, ethynylene (-C≡C-), propynylene (-CH2C≡C-), and the like. The alkynylene group can be optionally substituted with one or more substituents described herein.

[0075] The term "alkoxy" denotes an alkyl group, as described herein, attached to the rest of the molecule through an oxygen atom. Unless stated otherwise, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group can be optionally substituted with one or more substituents described herein.

[0076] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1 -propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1 -butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l -propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l -butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l -butoxy (-OCH2CH(CH3)CH2CH3), and the like.

[0077] The term "haloalkyl", "haloalkenyl", or "haloalkoxy" denotes an alkyl, alkenyl, or alkoxy group, respectively, substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoroethyl, 2,2,3,3-tetrafluoropropyl, trifluoromethoxy, and the like.

[0078] As used herein, the term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group has the definition as described herein. Examples of such include, but are not limited to, hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like.

[0079] The term "heteroalkyl" means an alkyl chain in which one or more of the carbon atoms are independently replaced with a heteroatom, wherein the alkyl group and the heteroatom have the definitions as described herein. Unless otherwise specified, a heteroalkyl group contains 1 to 10 carbon atoms, in other embodiments, a heteroalkyl group contains 1 to 8 carbon atoms, in other embodiments, a heteroalkyl group contains 1 to 6 carbon atoms, in other embodiments, a heteroalkyl group contains 1 to 4 carbon atoms, in other embodiments, a heteroalkyl group contains 1 to 3 carbon atoms. Examples of such include, but are not limited to, CH3OCH2-, CH3CH2OCH2-, CH3SCH2-, (CH3)2NCH2-, (CH3)2CH2OCH2-, CH3OCH2CH2-, CH3CH2OCH2CH2-, and the like.

[0080] As used herein, the term "cycloalkyl," unless otherwise specified, means a monovalent saturated or partially unsaturated (but not aromatic) monocyclic or polycyclic hydrocarbon. In some embodiments, the cycloalkyl group can be a bridged or unbridged, spirocyclic or non-spirocyclic, and / or fused or non-fused bicyclic group. In some embodiments, the cycloalkyl group comprises 3 to 10 carbon atoms, i.e., C3 to C10. In some embodiments, the cycloalkyl group comprises 3 to 8 carbon atoms, i.e., C3 to C8. In some embodiments, the cycloalkyl group comprises 3 to 6 carbon atoms, i.e., C3 to C6. In some embodiments, the cycloalkyl group comprises 3 to 4 carbon atoms, i.e., C3 to C4. In some embodiments, the cycloalkyl group comprises 3 to 7 carbon atoms, i.e., C3 to C7. In some embodiments, the cycloalkyl group comprises 3 to 5 carbon atoms, i.e., C3 to C5. In some embodiments, the cycloalkyl group comprises 3 to 4 carbon atoms, i.e., C3 to C4. In some embodiments, the cycloalkyl group comprises 3 carbon atoms, i.e., C3. In some embodiments, the cycloalkyl group comprises 4 carbon atoms, i.e., C4. In some embodiments, the cycloalkyl group comprises 5 carbon atoms, i.e., C5. In some embodiments, the cycloalkyl group comprises 6 carbon atoms, i.e., C6. In some embodiments, the cycloalkyl group comprises 7 carbon atoms, i.e., C7. In some embodiments, the cycloalkyl group comprises 8 carbon atoms, i.e., C8. In some embodiments, the cycloalkyl group comprises 9 carbon atoms, i.e., C9. In some embodiments, the cycloalkyl group comprises 10 carbon atoms, i.e., C10. In some embodiments, the cycloalkyl group is a monocyclic group. In some embodiments, the cycloalkyl group is a bicyclic group. In some embodiments, the cycloalkyl group is a tricyclic group. In some embodiments, the cycloalkyl group is a fully saturated group. In some embodiments, the cycloalkyl group is a partially saturated group. In some embodiments, the cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclo[2.1.1]hexyl group, a bicyclo[2.2.1]heptyl group, a decalinyl group, or an adamantyl group. When the cycloalkyl group is substituted, it can be independently substituted on any ring, i.e., on any aromatic or non-aromatic ring comprised by the cycloalkyl group, with one or more substituents described herein. 10 cycloalkyl. In some embodiments, the cycloalkyl group has 3 to 15 (C 3-15 ) carbon atoms. In some embodiments, the cycloalkyl group has 3 to 10 (C 3-10 ) carbon atoms. In some embodiments, the cycloalkyl group has 3 to 7 (C 3-7 ) carbon atoms. In some embodiments, the cycloalkyl group is a monocyclic group. In some embodiments, the cycloalkyl group is a bicyclic group. In some embodiments, the cycloalkyl group is a tricyclic group. In some embodiments, the cycloalkyl group is a fully saturated group. In some embodiments, the cycloalkyl group is a partially saturated group. In some embodiments, the cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclo[2.1.1]hexyl group, a bicyclo[2.2.1]heptyl group, a decalinyl group, or an adamantyl group. When the cycloalkyl group is substituted, it can be independently substituted on any ring, i.e., on any aromatic or non-aromatic ring comprised by the cycloalkyl group, with one or more substituents described herein.

[0081] The terms “heterocyclic group” and “heterocyclic” are used interchangeably herein, unless otherwise stated, referring to a monovalent monocyclic non-aromatic ring system and / or a polycyclic system comprising at least one non-aromatic ring; wherein one or more (in some embodiments, 1, 2, 3 or 4) of the non-aromatic monocyclic atoms are independently selected from O, S(O). 0-2 The heteroatoms of N and the remaining ring atoms are all carbon atoms; and one or more of the ring atoms in the polycyclic system (in some embodiments, 1, 2, 3 or 4) are independently selected from O, S(O). 0-2 The heterocycle contains one or two heteroatoms, all of which are nitrogen atoms. In some embodiments, the heterocycle comprises one or two heteroatoms, all of which are nitrogen atoms. In some embodiments, the heterocyclic group is polycyclic and contains one heteroatom in a non-aromatic ring, or one heteroatom in an aromatic ring, or two heteroatoms in an aromatic ring, or two heteroatoms, one in an aromatic ring and the other in a non-aromatic ring. In some embodiments, the heterocyclic group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms. In some embodiments, the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic system. In some embodiments, the heterocyclic group can be a bridged or non-bridged, spirocyclic or non-spirocyclic, and / or fused or non-fused bicyclic group. One or more nitrogen atoms and sulfur atoms may optionally be oxidized, one or more nitrogen atoms may optionally be quaternized, and one or more carbon atoms may optionally be... Substitution. Some rings can be partially or fully saturated, or aromatic, provided the heterocycle is not fully aromatic. The monocyclic heterocycle and polycyclic heterocycle can be attached to the main structure at any heteroatom or carbon atom that results in a stable compound. The polycyclic heterocycle group can be attached to the main structure through any of its rings, including any aromatic or non-aromatic ring, regardless of whether the ring contains a heteroatom. In some embodiments, a heterocyclyl group is a "heterocycloalkyl" which is 1) a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group containing at least one ring heteroatom as described herein, or 2) a saturated or partially unsaturated (but not aromatic) monovalent bicyclic or tricyclic group in which at least one ring contains at least one heteroatom as described herein. When a heterocyclyl and heterocycloalkyl group is substituted, it can be substituted on any ring, i.e., on any aromatic or non-aromatic ring contained within the heterocyclyl and heterocycloalkyl group. In some embodiments, such heterocyclyl groups include, but are not limited to, oxiranyl, azirdinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxoanyl, homopiperazinyl, homopiperidinyl, oxazepinyl, thiazepinyl, diazepinyl, oxazinyl, thiazinyl, diazinyl, triazinyl, tetrazinyl, oxazolidinonyl, thiazolidinonyl, oxazolidinyl, thiazolidinyl, imidazolidinonyl, imidazolidinyl, pyrazolidinonyl, pyrazolidinyl, triazolinyl, triazolinonyl, tetrazolinyl, tetrazolinonyl, and the like. In some embodiments, a heterocycloalkyl group is a "heterocycloalkyl ring" which is a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group containing at least one ring heteroatom as described herein. In some embodiments, a heterocycloalkyl group is a "heterocycloalkyl ring" which is a saturated or partially unsaturated (but not aromatic) monovalent bicyclic or tricyclic group in which at least one ring contains at least one heteroatom as described herein. In some embodiments, a heterocycloalkyl group is a "heterocycloalkyl ring" which is a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group containing at least one ring heteroatom as described herein. In some embodiments, a heterocycloalkyl group is a "heterocycloalkyl ring" which is a saturated or partially unsaturated (but not aromatic) monovalent bicyclic or tricyclic group in which at least one ring contains at least one heteroatom as described herein. In some embodiments, a heterocycloalkyl group is a "heterocycloalkyl ring" which is a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group containing at least one ring heteroatom as described herein. In some embodiments, a heterocycloalkyl group is a "heterocycloalkyl ring" which is a saturated or partially unsaturated (but not aromatic) monovalent bicyclic or tricyclic group in which at least one ring contains at least one heteroatom as described herein. benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, dihydrobenzofuranyl, benztetrahydrothiophenyl, benzothiopyranyl, benzoxazinyl, beta-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroquinolinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, 2,4-dioxo-imidazolidinyl, imidazolinyl, indolinyl, 2-oxo-indolinyl, isobenztetrahydrofuranyl, isobenzotetrahydrothiophenyl, isochromanyl, isocoumarinyl, isoindolinyl (isoindolinonyl), 1-oxo-isoindolinyl, 1,3-dioxo-isoindolinyl, isothiazolidinyl, isoxazolidinyl, 3-oxo-isoxazolidinyl, morpholinyl, 3,5-dioxo-morpholinyl, octahydroindolyl, octahydroisoindolyl, 1-oxo-octahydroisoindolyl, 1,3-dioxo-hexahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, 2,6-dioxo-piperazinyl, piperidinyl, 2,6-dioxo-piperidinyl, 4-piperidonyl, 2-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, quinuclidinyl, tetrahydroisoquinolinyl, 3,5-dioxo-thiomorpholinyl, thiazolidinyl, 2,4-dioxo-thiazolidinyl, tetrahydroquinolinyl, thiazinyl, thioxanthyl, xanthenyl, and 1,3,5-trithianyl. Examples of heterocyclyl groups in which a -CH2- group is replaced by a -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidinedionyl. Examples of heterocyclyl groups in which a sulfur atom is oxidized include, but are not limited to, a sulfolanyl group, a 1,1-dioxothiomorpholinyl group. The recited heterocyclyl groups can be optionally substituted with one or more substituents described herein.

[0082] In one embodiment, the heterocyclic group is a heterocyclic group consisting of 3-8 atoms, referring to a saturated or partially unsaturated monocycle containing 3-8 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise stated, the heterocyclic group consisting of 3-8 atoms can be carbonyl or nitrogenyl, and the -CH2- group can optionally be replaced by -C(=O)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxide compound. Examples of heterocyclic groups consisting of 3-8 atoms include, but are not limited to: azirobutyl, oxacyclobutyl, thioherobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxane, dithiaalkyl, thiaalkyl, homopiperazine, homopiperidinyl, oxacycloheptyl, thioheptanyl, oxacycloheptyl, oxacycloheptyl, oxacycloheptyl, oxacycloheptyl 2-diazine Base, sulfur nitrogen Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridine, and pyrimidinidone. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholino. The heterocyclic group consisting of 3-8 atoms may optionally be replaced by one or more substituents described in this invention.

[0083] In one embodiment, the heterocyclic group is a heterocyclic group consisting of 3-6 atoms, referring to a saturated or partially unsaturated monocycle containing 3-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise stated, the heterocyclic group consisting of 3-6 atoms can be carbonyl or nitrogenyl, and the -CH2- group can optionally be replaced by -C(=O)-. The sulfur atom of the ring can optionally be oxidized to an S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxide. The heterocyclic group consisting of 3-6 atoms can optionally be substituted by one or more substituents described in this invention.

[0084] In another embodiment, heterocyclyl refers to a 5-6 membered heterocyclyl group, which means a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms, at least one of which is selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise indicated, the 5-6 membered heterocyclyl group can be carbon-based or nitrogen-based, and the -CH2- group can optionally be replaced with -C(=O)-. The sulfur atom of the ring can optionally be oxidized to the S-oxide or S-oxide. The nitrogen atom of the ring can optionally be oxidized to the N-oxide. Examples of 5-6 membered heterocyclyl groups include, but are not limited to, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanyl, dithiolyl, 2-oxopyrrolidinyl, oxo-l,3-thiazolidinyl, cyclobutylsulfolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, 2-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidinedionyl, 1,1-dioxothiomorpholinyl. The 5-6 membered heterocyclyl groups described can optionally be substituted with one or more substituents described herein.

[0085] The term "cycloalkylalkyl" means an alkyl group which can be substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl have the meanings as described herein. Examples include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylethyl and the like.

[0086] The term "heterocyclylalkyl" includes heterocyclyl-substituted alkyl groups; the term "heterocyclylalkoxy" includes heterocyclyl-substituted alkoxy groups, wherein the oxygen atom is attached to the remainder of the molecule; the term "heterocyclylalkylamino" includes heterocyclyl-substituted alkylamino groups, wherein the nitrogen atom is attached to the remainder of the molecule. Examples include, but are not limited to, azetidin-l-ylmethyl, azetidin-l-ylethyl, azetidin-l-ylpropyl, pyrrol-l-ylmethyl, pyrrol-l-ylethyl, pyrrol-l-ylpropyl, morpholin-4-ylethyl, morpholin-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino and the like, wherein heterocyclyl, alkyl, alkoxy and alkylamino have the meanings as described herein.

[0087] The terms "fused bicyclic", "fused ring", "fused bicyclic group", "fused ring group" mean a saturated or unsaturated fused ring system, involving a non-aromatic bicyclic system, as shown in formula (al), i.e., ring B shares a bond with ring B'. Such systems can contain independent or conjugated unsaturation, but the core structure does not contain an aromatic or heteroaromatic ring (although aromaticity can exist as a substituent thereon). Each ring in a fused bicyclic ring is either carbocyclic or heteroaliphatic, examples of which include, but are not limited to, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-lH-indene, 7-azabicyclo[2.3.0]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, which are encompassed within fused bicyclic rings. Also, the fused bicyclic group can be substituted or unsubstituted, where the substituents can be, but are not limited to, D, F, Cl, Br, I, N3, CN, NO2, OH, SH, NH2, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(=O)nRm, -OS(=O)nRm, -C(=O)Rm, -OC(=O)Rm, -C(=O)ORm, -NRnC(=O)Rm, -C(=O)NRnRm, -OC(=O)NRnRm, -NRnRm, -N(Rn)S(=O)nRm, -N(Rn)C(=O)NRpRq, -Rn, -S(=O)nRm, -C(=O)Rm, -OS(=O)nRm, -OC(=O)Rm, -N(Rn)C(=O)Rm, or -Rn, where n is 0 to 2, m and r are independently H, D, C1-C10alkyl, C1-C10haloalkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C3-C10cycloalkenyl, heterocyclyl, aryl, heteroaryl, or -P(=O)2H2, and p and q are independently H, D, C1-C10alkyl, C1-C10haloalkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, C3-C10cycloalkenyl, heterocyclyl, aryl, heteroaryl, or -P(=O)2H2. 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -C(=O)NR 9a R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , -R 14 -N(R 13 )C(=O)NR 13a R 13b and the like, wherein R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , R 10a , R 11 , R 11a , R 12 , R 12a , R 13 , R 13a , R 13b and R 14 have the definitions given in the application.

[0088]

[0089] The term "fused heterobicycyl" refers to a saturated or unsaturated fused or bridged ring system, involving a non-aromatic bicyclic or bridged ring system. Such systems can contain independent or conjugated unsaturation, but the core structure does not contain an aromatic or heteroaromatic ring (although aromaticity can be present as a substituent thereon). And at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 members, i.e., contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P are optionally substituted by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2, examples of which include, but are not limited to, hexahydro-furo[3,2-b]furan, 7-azabicyclo[2.3.0]heptane, 2-azabicyclo[2.2.1]heptane, octahydro-pyrrolo[3,2-b]pyrrole, octahydro-pyrrolo[3,4-c]pyrrole, octahydro-lH-pyrrolo[3,2-b]pyridine, and the like. And the fused heterobicycyl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, D, F, Cl, Br, I, N3, CN, NO2, OH, SH, NH2, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(=O) 0-2R 7 , -C(=O)R 8 , -OS(=O) 1- 2R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -C(=O)NR 9a R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , -R 14 -N(R 13 )C(=O)NR 13a R 13b and the like, wherein R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , R 10a , R 11 , R 11a , R 12 , R 12aR 13 R 13a R 13b R 14 R 0-2 R 7 R 8 R 1-2 R 7a R 8a R 8a R 9a R 9 R 9a R 9 R 10 R 10a R 11 R 11a R 12 R 1-2 R 12a R 13 R 13a R 13b R 14 R 0-2 R 7 R 14 R 8 R 14 R 1-2 R 7a R 14

[0090] The term "spirocyclyl", "spirocycle", "spirobicyclyl", "spirobicycle" means one ring is born from a special ring carbon of another ring. For example, ring A and ring B share one carbon atom in a two saturated ring system, then it is called "spirocycle". Each ring inside the spirocycle is either carbocyclic or heteroaliphatic. Examples of such include, but are not limited to, 2,7-diazaspiro[4.4]nonan-2-yl, 7-oxa-2- azaspiro[4.5]dec-2-yl, 4-azaspiro[2.4]heptan-5-yl, 4-oxaspiro[2.4]heptan-5-yl, 5- azaspiro[2.4]heptan-5-yl, spiro[2.4]heptyl, spiro[4.4]nonanyl, 7-hydroxy-5-azaspiro[2.4]heptan-5-yl, and the like. Also, the spirobicyclyl group can be substituted or unsubstituted, where the substituents can be, but are not limited to, D, F, Cl, Br, I, N3, CN, NO2, OH, SH, NH2, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(=O)R 0-2 7 8 1-2 7a 8a 8a 9a 9 9a 9 10 10a 11 11a 12 1-2 12a 13 13a 13b 14 0-2 7 14 8 14 1-2 7a 14-OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , -R 14 -N(R 13 )C(=O)NR 13a R 13b and the like, wherein R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , R 10a , R 11 , R 11a , R 12 , R 12a , R 13 , R 13a , R 13b and R 14 have the definition given in the present application.

[0091]

[0092] The term "spiro bicyclic group" denotes a bicyclic ring system having two points of attachment to the rest of the molecule, wherein the bicyclic group has the definition given in the present application.

[0093] The term "spiroheterocyclic group" indicates that one ring originates from a specific cyclic carbon atom on another ring. For example, as described above, rings A and B share a carbon atom in two saturated ring systems, which is called a "spirocycle". At least one ring system contains one or more heteroatoms, wherein each ring system contains a 3-7 membered ring, i.e., containing 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO2, PO, PO2. Examples of such groups include, but are not limited to, 4-azaspiro[2.4]heptane-5-yl, 4-oxaspiro[2.4] Heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl, 7-hydroxy-5-azaspiro[2.4]heptane-5-yl, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 1,6-diazaspiro[3.4]octane, 2,7-diazaspiro[3.5]nonane, 1,7-diazaspiro[3.5]nonane, 3,9-diazaspiro[5.5]undecane, etc. Furthermore, the spiro-acyclic bicyclic group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, D, F, Cl, Br, I, N3, CN, NO2, OH, SH, NH2, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -S (=O). 0-2 R 7 -C(=O)R 8 -OS (=O) 1-2 R 7a -OC(=O)R 8a -C(=O)OR 8a -N(R) 9a )C(=O)R 9 -C(=O)NR 9a R 9 -OC(=O)NR 10 R 10a -NR 11 R 11a -N(R) 12 S(=O) 1-2 R 12a -N(R) 13 )C(=O)NR 13a R 13b -R 14 -S(=O) 0-2 R 7 -R 14 -C(=O)R 8 -R 14 -OS(=O) 1-2 R 7a -R14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , -R 14 -N(R 13 )C(=O)NR 13a R 13b and the like, wherein R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , R 10a , R 11 , R 11a , R 12 , R 12a , R 13 , R 13a , R 13b and R 14 have the definitions given in the application.

[0094] The term "bridged ring group" as used herein refers to a saturated or unsaturated bridged ring system, and relates to non-aromatic bridged ring systems, as shown in formula (a2), i.e., ring A1 shares an alkyl chain or a heteroalkyl chain with ring A2, wherein j is 1, 2, 3 or 4. Such systems can contain independent or conjugated unsaturation, but the core structure does not contain an aromatic or heteroaromatic ring (although aromaticity can be present as a substituent thereon). Each ring in the bridged ring is either carbocyclic or heteroalicyclic, examples of which include, but are not limited to, bicyclo[2.2.1]heptane, 2-azabicyclo[2.2.1]heptane, 1,2,3,4,4a,5,8,8a-octahydronaphthalene, which are included within the fused bicyclic or bridged ring systems. Also, the bridged ring group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, D, F, Cl, Br, I, N3, CN, NO2, OH, SH, NH2, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(=O) 0-2 R 7 , -C(=O)R8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -C(=O)NR 9a R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , -R 14 -N(R 13 )C(=O)NR 13a R 13b and the like, wherein X 3 , R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , R 10a , R 11 , R 11a , R 12 , R 12a , R13 R 13a R 13b R 14 have the definitions as described in the application.

[0095]

[0096] The term "bridged heterocyclyl" denotes a saturated or unsaturated bridged ring system, involving a non-aromatic bridged ring system. Such systems can contain independent or conjugated unsaturation, but the core structure does not contain an aromatic or heteroaromatic ring (although aromaticity can be present as a substituent thereon). And at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 members, i.e., contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P are optionally substituted by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2, examples of which include, but are not limited to, 2-azabicyclo[2.2.1]heptane, (1R,5S)-3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, (1R,5S)-8-azabicyclo[3.2.1]octane, and the like. And the bridged heterocyclyl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, D, F, Cl, Br, I, N3, CN, NO2, OH, SH, NH2, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(=O) 0-2 R 7 -C(=O)R 8 -OS(=O) 1-2 R 7a -OC(=O)R 8a -C(=O)OR 8a -N(R 9a )C(=O)R 9 -C(=O)NR 9a R 9 -OC(=O)NR 10 R 10a -NR 11 R 11a -N(R 12 )S(=O) 1-2 R 12a -N(R 13 )C(=O)NR 13a R 13b -R 14 -S(=O) 0-2 R 7 -R 14 -C(=O)R8 14 1-2 7a 14 8a 14 9a 9 14 10 10a 14 11 11a 14 12 1-2 12a 14 13 13a 13b wherein R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , R 10a , R 11 , R 11a , R 12 , R 12a , R 13 , R 13a , R 13b and R 14 have the meaning as described in the present application.

[0097] As described in the present application, there are two points of attachment in the ring system to the rest of the molecule, as shown in formula (a3) or (a4), which means that either the E end or the E' end can be attached to the rest of the molecule, i.e. the attachment can be interchanged.

[0098] E-N(R g )C(=O)O-E' (a4)

[0099] The term "n-membered", wherein n is an integer, typically describes the number of atoms in a ring in a molecule, in which the number of atoms in the ring in the molecule is n. For example, piperidinyl is a 6-membered heterocycloalkyl group, while 1,2,3,4-tetrahydronaphthalene is a 10-membered cycloalkyl group. The term "unsaturated" as used in the present application means that the group contains one or more degrees of unsaturation.

[0100] ​​​​​​​​​​​​​​​​​​​​​​The term "heteroatom" means O, S, N, P, and Si, including forms of N, S, and P in any oxidation state; forms of primary, secondary, tertiary amines and quaternary ammonium salts; or forms in which the hydrogen on a nitrogen atom in a heterocycle is replaced, for example, by N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl).

[0101] The term "halogen" means fluorine (F), chlorine (CI), bromine (Br), or iodine (I).

[0102] The term "aryl," as used herein, means a monovalent C6-C30hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a C6-C30aryl ring system. The aryl group can be substituted or unsubstituted. The aryl group can be attached to the main structure through any ring thereof. In some embodiments, the aryl group is phenyl, naphthyl, bicyclo[4.2.0]octa-l,3,5-trienyl, indanyl, fluorenyl, or tetrahydronaphthyl. When the aryl group is substituted, it can be substituted on any ring thereof. In some or any embodiments, the aryl group is phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, or indanyl; each of the phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, and indanyl is optionally substituted with one or more substituents independently selected from the substituents described herein, including, in some embodiments, D, F, CI, Br, I, N3, CN, NO2, OH, SH, NH2, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(=O)R 14 The term "heteroatom" means O, S, N, P, and Si, including forms of N, S, and P in any oxidation state; forms of primary, secondary, tertiary amines and quaternary ammonium salts; or forms in which the hydrogen on a nitrogen atom in a heterocycle is replaced, for example, by N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1- 2R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -C(=O)NR 9a R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O)0-2 R 7 R 14 R 8 R 14 R 1-2 R 7a R 14 R 8a R 14 R 9a R 9 R 14 R 10 R 10a R 14 R 11 R 11a R 14 R 12 R 1-2 R 12a R 14 R 13 R 13a R 13b R 7 R 7a R 8 R 8a R 9 R 9a R 10 R 10a R 11 R 11a R 12 R 12a R 13 R 13a R 13b R 14

[0103] The term "aralkyl," as used herein, unless otherwise indicated, means an alkyl group substituted with one or two aryl groups, as defined herein, wherein the alkyl group is the point of attachment to the rest of the molecule. In some embodiments, the aralkyl group is a benzyl, phenethyl-1-yl, phenethyl-2-yl, diphenylmethyl, 2,2-diphenylethyl, 3,3-diphenylpropyl, or 3-phenylpropyl; each of which is optionally substituted on the ring with one or more substituents described herein.

[0104] ​The term "heteroaryl" as used in this invention, unless otherwise stated, refers to a monovalent monocyclic or polycyclic aromatic group, wherein at least one (in some embodiments, 1, 2, 3, or 4) ring atom is independently selected from O, S(O) in the ring. 0-2 The heteroaryl group is a heteroatom of N. The heteroaryl group is attached to the remainder of the molecule by any atom in the ring system, where the valence rules allow. In some embodiments, each ring of the heteroaryl group may contain 1 or 2 O atoms, 1 or 2 S atoms, and / or 1 to 4 N atoms, or combinations thereof, provided that the total number of heteroatoms in each ring is 4 or less, and each ring contains at least 1 carbon atom. In some embodiments, the heteroaryl group has 5-20, 5-15, or 5-10 ring atoms. When the heteroaryl group is substituted, it may be substituted on any ring. In some embodiments, the monocyclic heteroaryl group includes, but is not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroleyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl, and triazolyl. In some embodiments, the bicyclic heteroaryl group includes, but is not limited to, benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzooxazolyl, furanopyridyl, imidazopyridyl, imidazothiazolyl, indazinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiaphenyl, isoindolyl, isoquinolinyl, isothiazolyl, naphridyl, oxazolopyridyl, phthalazinyl, pteridinyl, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalolinyl, quinazolinyl, thiadiazolopyrimidinyl, and thiophenopyridyl. In some embodiments, the tricyclic heteroaryl group includes, but is not limited to, acridinel, benzoindolyl, carbazolel, dibenzofuranyl, vinidinel, phenanthrolinel, phenanthidinel, and phenazinyl. In some or any embodiments, the heteroaryl group is indolyl, furanyl, pyridinyl, pyrimidinyl, imidazolyl, or pyrazolyl; each optionally substituted with one, two, three, or four groups defined throughout this specification, including, in some embodiments, groups independently selected from D, F, Cl, Br, I, N3, CN, NO2, OH, SH, NH2, alkyl, haloalkyl, alkenyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -S (=O). 0- 2R 7 -C(=O)R 8 -OS (=O) 1-2 R 7a -OC(=O)R 8a -C(=O)OR 8a -N(R) 9a )C(=O)R 9 -C(=O)NR9a R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , -R 14 -N(R 13 )C(=O)NR 13a R 13b and the like, wherein R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , R 10a , R 11 , R 11a , R 12 , R 12a , R 13 , R 13a , R 13b and R 14 have the definitions given in the present application.

[0105] The term "heteroarylalkyl," as used herein, means an alkyl group, as defined herein, substituted with one or two heteroaryl groups, as defined herein, wherein the alkyl group is the point of attachment to the rest of the molecule. Examples of heteroarylalkyl groups include, but are not limited to, imidazol-2-ylmethyl, thiazol-2-ylmethyl, furan-2-ylethyl, indol-3-ylmethyl, and the like; each of which is optionally substituted on any ring with one or more substituents described herein.

[0106] The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino," wherein the amino group is independently substituted with one or two alkyl groups, respectively. Some embodiments are where the alkylamino group is a C 1-6 lower alkylamino group having an alkyl group attached to the nitrogen atom. Other embodiments are where the alkylamino group is a C 1-3 lower alkylamino group having an alkyl group attached to the nitrogen atom. Other embodiments are where the alkylamino group is a C

[0107] The term "aminoalkyl" includes a C 1-10 straight or branched chain alkyl group substituted with one or more amino groups. Some embodiments are where the aminoalkyl group is a C 1-6 "lower aminoalkyl," other embodiments are where the aminoalkyl group is a C 1-4 "lower aminoalkyl," such as, but not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

[0108] The term "cyano-substituted alkyl" includes a C 1-10 straight or branched chain alkyl group substituted with one or more cyano groups. Some embodiments are where the cyano-substituted alkyl group is a C 1-6 "lower cyanoalkyl," other embodiments are where the cyano-substituted alkyl group is a C 1-4 "lower cyanoalkyl," such as, but not limited to, CNCH2-, CNCH2CH2-, CNCH2CH2CH2-, CNCH2CHCNCH2-, and the like.

[0109] As depicted in the present application, the substituents drawn as a bond to the central ring forming ring system (as shown in the figure below) represent that the substituents can be substituted at any substitutable position on any ring. For example, formula b represents that any substitutable position on ring A or ring B can be substituted, such as shown in formulas c, d, e, f, g, h, i, j, k, 1, m, n, o, p, q, etc.

[0110]

[0111] The term "prodrug" as used herein refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is effected by the hydrolysis of the prodrug in the blood or by enzymatic conversion in the blood or tissue to the parent structure. The prodrug class of compounds of the present application can be esters, and in the present application the esters that can act as prodrugs are benzoic acid esters, aliphatic (Ci-C 24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present application containing a hydroxyl group can be acylated to give a compound in the form of a prodrug. Other prodrug forms include phosphates, such as these phosphate compounds are phosphorylated on the hydroxyl group of the parent. A complete discussion of prodrugs can be found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0112] "Metabolite" refers to a product produced through metabolism of a specified compound or salt thereof in the body. Metabolites of a compound can be identified using techniques known in the art, and can be tested using assays described herein or otherwise known to those skilled in the art. Such products can result for example from oxidative, reduc tive, hydrolytic, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like. Accordingly, the present application includes metabolites of compounds of the present application, including those produced following administration of the compound to a mammal for a period of time sufficient to yield a metabolic product.

[0113] "Pharmaceutically acceptable salt" as used herein refers to organic and inorganic salts of the compounds of the present application. Pharmaceutically acceptable salts are well known in the art, for example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable, non-toxic salts include, but are not limited to, salts of inorganic acids such as hydrochloride, hydrobromide, phosphate, sulphate, hydrogensulphate, and organic acids such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods such as ion exchange procedures as described in the literature. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulphonate, benzoate, bisulphate, borate, butyrate, camphorate, camphorsulphonate, cyclopentanepropionate, digluconate, dodecylsulphate, ethanesulphonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulphate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulphonate, lactobionate, lactate, laurate, lauryl sulphate, malate, malonate, mesylate, 2-naphthalenesulphonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulphate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulphonate, undecanoate, valerate, and the like. Salts with appropriate amines include, but are not limited to, salts of +(C1-C4alkyl)4. The present application is also intended to contemplate quaternary ammonium salts of any of the compounds containing N. Water or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, nontoxic organic or inorganic acid addition salts including, but not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, nitric, phosphoric, and the like; and the salts derived from organic acids such as, but not limited to, acetic, propionic, lactic, malonic, benzoic, cinnamic, citric, pyruvic, malic, succinic, fumaric, maleic, hydroxymaleic, mandelic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, cyclamic, salicylic, and the like; or salts derived from amino acids such as, but not limited to, glycine, alanine, valine, leucine, and the like. 1-8 sulfates, phosphates, nitrates, C

[0114] The "solvate" of the present application refers to an association or complex of one or more solvent molecules with a compound of the present application. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to the complex where the solvent molecule is water.

[0115] The term "hydrate" can be used when the solvent is water. In some embodiments, one molecule of a compound of the present application can be associated with one molecule of water, such as a monohydrate; in other embodiments, one molecule of a compound of the present application can be associated with more than one molecule of water, such as a dihydrate, and in yet other embodiments, one molecule of a compound of the present application can be associated with less than one molecule of water, such as a hemihydrate. It is noted that the hydrates of the present application retain the bioavailability of the compound in its non-hydrated form.

[0116] The term "treat" or "treatment" of any disease or condition, as used herein, in some embodiments, means to ameliorate the disease or condition (i.e., to slow or arrest or reduce the development of the disease or at least one of the clinical symptoms thereof). In other embodiments, "treatment" means to alleviate or ameliorate at least one physical parameter including, but not limited to, a parameter not discernible by the patient. In other embodiments, "treatment" means to mediate a disease or condition either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In other embodiments, "treatment" means to prevent or delay the onset or development of a disease or condition. SUMMARY

[0118] The present application provides aryl heterocyclic compounds that effectively inhibit ATX activity and are useful for the preparation of a medicament for treating a disease having an increased expression of ATX as a pathological feature, such as cancer, fibrotic diseases (e.g., idiopathic pulmonary fibrosis or liver fibrosis), metabolic diseases, myelodysplastic syndrome, cardiovascular diseases, autoimmune diseases, inflammation, nervous system diseases, or pain.

[0119] In one aspect, the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitroso, metabolite, prodrug, or mixture of the compound of Formula (I):

[0120]

[0121] wherein,

[0122] W is -N(R 1a )-, -O-, -S-, -S(=O) 1-2 -, -C(=O)-, -(C(R 2a )(R 2b )) 1-4 -, -N(R 1a )(C(R 2a )(R 2b )) 1-4 -, -N(R 1a )C(=O)-, or -O(C(R 2a )(R 2b )) 1-4 -;

[0123] Ar 1 and Ar 2 are each independently a five-membered heteroaryl group, wherein Ar 1 and Ar 2 are independently optionally substituted with 1, 2, or 3 R 2 ;

[0124] Ar 3 is an aryl group, or a heteroaryl group, wherein the Ar 3 is independently optionally substituted with 1, 2, 3, or 4 R 3 ;

[0125] Cy is a cycloalkyl group, a heterocyclyl group, a spirobicycyl group, a spiroheterobicyclyl group, a fused bicyclyl group, a fused heterobicyclyl group, a bridged cycloalkyl group, a bridged heterocyclyl group, an aryl group, or a heteroaryl group, wherein the Cy is optionally substituted with 1, 2, 3, or 4 R 4 ;

[0126] Y is -(L 1 -W 1 ) m -L 2 -;

[0127] L 1 is absent, or L 1 is -O-, -C(=O)-, -N(R i )-, -N(R h )C(=O)-, or -S(=O)0-2 -;

[0128] W 1 C; 1-4 alkylene, said C 1-4 alkylene is optionally substituted with 1, 2, 3, or 4 groups independently selected from H, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, and C 1-6 alkoxy;

[0129] L 2 is absent, or L 2 is -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)-C(=O)-, -C(=O)-C(=O)N(R a )-, -N(R b )-, -C(=O)N(R c )-, -N(R c )C(=O)-, -C(=O)N(R c )-R 15 -C(=O)O-, -C(=O)N(R c )-R 15 -C(=O)N(R a )-, -N(R d )C(=O)N(R c )-, -N(R g )C(=O)O-, -S(=O) 0-2 -, -S(=O) 1-2 N(R e )-, -N(R f )S(=O) 1-2 -, or -N(R f )S(=O) 1-2 -R 15 -N(R a )-;

[0130] Z is H, -CN, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, spirobicyclyl, spiroheterobicyclyl, fused bicyclyl, fused heterobicyclyl, bridged ring, bridged heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, spirobicyclyl, spiroheterobicyclyl, fused bicyclyl, fused heterobicyclyl, bridged cycloalkyl, bridged heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R 5 ;

[0131] R 1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein said R 1independently optionally substituted with 1, 2, 3, or 4 R 6 substituted;

[0132] each R 2 is independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxyalkyl, aryloxyalkyl, haloalkoxy, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b ;

[0133] R2a and R 2b each independently H, -CN, -OH, -NH2, F, Cl, Br, I, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryl, aralkyl, heteroaryl, or heteroarylalkyl;

[0134] each R 3 is independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, haloalkoxy, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1- 2R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1- 2R 12a , or -R 14 -N(R 13 )C(=O)NR13a R 13b ;

[0135] each R 4 is independently H, oxo (C=0), -CN, -N02, -OH, -NH2, F, CI, Br, I, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, haloalkoxy, -S(=0) 0-2 R 7 , -C(=0)R 8 , -OS(=0) 1-2 R 7a , -C(=0)OR 8a , -OC(=0)R 8a , -N(R 9a )C(=0)R 9 , -C(=0)NR 9a R 9 , -OC(=0)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=0) 1-2 R 12a , -N(R 13 )C(=0)NR 13a R 13b , -R 14 -S(=0) 0-2 R 7 , -R 14 -C(=0)R 8 , -R 14 -OS(=0) 1-2 R 7a , -R 14 -OC(=0)R 8a , -R 14 -N(R 9a )C(=0)R 9 , -R 14 -OC(=0)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=0) 1-2 R 12a , or -R 14 -N(R 13 )C(=0)NR 13a R 13b ;

[0136] each R 5 is independently H, oxo (C=0), -CN, -N02, -OH, -NH2, F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkylamino, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryl, aralkyl, -S(=0) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b ;

[0137] each R 6each R is independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkoxy, haloalkoxy, -S(=O)nR 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1- 2R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1- 2R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b ;

[0138] each R is independently H, C 7 , R 7a , R 8 , R 8a , R 9 , and R 12a are each independently H, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl and cyano substituted C 1-6 Alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, or heterocyclic alkyl;

[0139] Each R 9a R 10 and R 10a H and C are independent of each other. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 C60 with alkynyl or cyano substitution 1-6 Alkyl or halogenated C 1-6 alkyl;

[0140] Each R 11 and R 11a H and C are independent of each other. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl and cyano substituted C 1-6 Alkyl or aralkyl;

[0141] Each R 12 R 13 R 13a and R 13b H and C are independent of each other. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 C60 with alkynyl or cyano substitution 1-6 Alkyl or halogenated C 1-6 alkyl;

[0142] R 1a Each of the following can be independently H, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;

[0143] Each R a R b R c R d R e R f R g R h and R i Alkyl groups, haloalkyl groups, and R groups that are independently substituted with H, alkyl, alkenyl, ynyl, or cyano groups, respectively. 16 -C(=O)-, or cycloalkylalkyl;

[0144] Each R 14and R 15 each independently is alkylene, alkenylene, alkynylene, cyano-substituted alkyl, or haloalkylene;

[0145] R 16 is H, C 1-6 alkyl or haloC 1-6 alkyl; and

[0146] m is 0, 1, or 2.

[0147] In some embodiments, wherein Ar 3 is C 6-10 aryl or C 1-9 heteroaryl, wherein the Ar 3 is independently and optionally substituted with 1, 2, 3, or 4 R 3 .

[0148] In other embodiments, wherein Ar 3 is:

[0149]

[0150] wherein X 1 is -O-, -S-, -N(R 3 )-, -N=C(R 3 )-, -C(R 3 )=N-, or -C(R 3 )=C(R 3 )-; and

[0151] Y 1 , Y 1a , and Y 2 are each independently -N-, -CH-, or -C(R 3 )-.

[0152] In other embodiments, wherein Ar 3 is

[0153]

[0154] wherein the Ar 3 is independently and optionally substituted with 0, 1, or 2 R 3 .

[0155] In some embodiments, the compounds of the present application have the structure of formula (Ia):

[0156]

[0157] wherein,

[0158] X 1 is -O-, -S-, -N(R3 )-, -N=C(R 3 )-, -C(R 3 )=N-, or -C(R 3 )=C(R 3 )-;

[0159] Y 1 and Y 2 are each independently -N-, or -C(R 3 )-;

[0160] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitroso, metabolite, prodrug, or mixture thereof.

[0161] In some embodiments, wherein: the ring consisting of Ar 1 and Ar 2 is

[0162]

[0163] wherein,

[0164] X 2 is -O-, -S-, -C(R 2 )(R 2c )-, or -N(R 2d )-;

[0165] Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently -N-, or -C(R 2 )-;

[0166] R 2c is H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, aralkoxyC 1-4 alkyl, C 6-10 aryloxyC 1-4 alkyl, -S(=O) 0-2 R 7 , -C(=O)R​8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0- 2R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b ;

[0167] R 2d is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano-substituted C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy C 1-4 alkyl, aralkoxy C 1-4 alkyl, C 6-10 aryloxy C 1-4 alkyl, -S(=O) 0-2 R7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , or -OC(=O)NR 10 R 10a , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b ; and

[0168] each R 14 is independently C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, cyano-substituted C 1-4 alkylene, or halogenated C 1-4 alkylene.

[0169] In other embodiments, the ring consisting of Ar 1 and Ar 2 is

[0170]

[0171] wherein,

[0172] X 2 is -O-, -S-, -C(R 2 )(R 2c )-, or -N(R 2d )-;​

[0173] Y 3 is -N-, or -C(R 2 )-;

[0174] Y 6 is -N-, or -C(R 2 )-;

[0175] R 2c is H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, aralkoxyC 1-4 alkyl, C 6-10 aryloxyC 1-4 alkyl, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0- 2R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b ;

[0176] R 2d is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano-substituted C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -OC(=O)NR 10 R 10a , -R 14 -S(=O) 0- 2R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b ; and

[0177] each R 14C independently 1-4 Alkylene, C 2-4 imidene group, C 2-4 C-substituted with ynyl or cyano groups 1-4 Alkylene or halogenated C 1-4 Alkylene.

[0178] In other implementation schemes, where Ar 1 and Ar 2 Composition Ring for

[0179]

[0180] Where n is 0, 1 or 2.

[0181] In some implementation schemes, R 1 C 6-10 Aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl, or C 2-9 Heterocyclic groups, wherein the R 1 Independently and optionally by 1, 2, 3 or 4 R 6 replace.

[0182] In some implementation schemes, R 1 C 6-10 Aryl, C 1-9 heteroaryl, C 3-6 cycloalkyl, or C 2-7 Heterocyclic groups, wherein the R 1 Independently and optionally by 1, 2, 3 or 4 R 6 replace.

[0183] In other implementation schemes, R 1 It is phenyl or pyridyl, wherein the phenyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. 6 replace.

[0184] In some embodiments, the compounds of the present invention have the structure shown in formula (Ib):

[0185]

[0186] in,

[0187] X 1 -O-, -S-, -N(R) 3 )-、-N=C(R 3 )-、-C(R 3 ) = N-, or -C(R) 3 )=C(R 3 )-;

[0188] X 2 is -O-, -S-, -C(R 2 )(R 2c )-, or -N(R 2d )-;

[0189] Y 1 and Y 2 are each independently -N-, or -C(R 3 )-;

[0190] Y 3 , Y 4 , Y 5 , and Y 6 are each independently -N-, or -C(R 2 )-;

[0191] t is 0, 1, 2, 3, or 4;

[0192] R 2c is H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, aralkoxyC 1-4 alkyl, C 6-10 aryloxyC 1-4 alkyl, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0- 2R 7 , -R14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b ;

[0193] R 2d is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -OC(=O)NR 10 R 10a , -R 14 -S(=O) 0- 2R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14-NR 11 R 11a -R 14 -N(R 12 S(=O) 1-2 R 12a or -R 14 -N(R 13 )C(=O)NR 13a R 13b ;and

[0194] Each R 14 C independently 1-4 Alkylene, C 2-4 imidene group, C 2-4 C-substituted with ynyl or cyano groups 1-4 Alkylene or halogenated C 1-4 Alkylene; or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, or mixture.

[0195] In some implementations, W is -N(R) 1a - or -C(R) 2a (R) 2b )-;R 1a For H, C 1-4 Alkyl or halogenated C 1-4 Alkyl; R 2a and R 2b Each of the following can be independently H, -CN, -OH, -NH2, F, Cl, Br, I, C 1-4 Alkyl, Halogenated C 1-4 alkyl and cyano substituted C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 6-10 Aryl, C 6-10 Aryl C 1-4 Alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-4 alkyl.

[0196] In some implementations, W is -N(R) 1a )-;R 1a It can be H, methyl, ethyl, propyl, -CF3, or -CH2CF3.

[0197] In some implementation schemes,

[0198] X 1 -O-, -S-, -N(R) 3 )-、-N=C(R 3 )-、-C(R3 ) = N-, or -C(R 3 ) = C(R 3 )-;

[0199] Y 1 and Y 2 are each independently -N-, or -C(R 3 )-;

[0200] each R 3 is independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, C 1-4 alkyl, haloC 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O)1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b ;

[0201] each R 7 , R 7a , R 8 , R 8a , R 9 , and R 12a is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, cyano-substituted C 1-4 alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl;

[0202] each R 9a , R 10 , and R 10a is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano-substituted C 1-4 alkyl, or haloC 1-4 alkyl;

[0203] each R 11 and R 11a is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, cyano-substituted C 1-4 alkyl, or C 6-10 arylC 1-6 alkyl;

[0204] each R 12 , R 13 , R 13a , and R 13b is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano-substituted C 1-4 alkyl, or haloC 1-4 alkyl; and

[0205] each R 14 is independently C 1-4 alkylene, C 2-4 alkenylene, C 2-4alkynylene, cyano-substituted C 1-4 alkylene, or halo-substituted C 1-4 alkylene.

[0206] In some embodiments, the compound of the application has the structure of Formula (Ic):

[0207]

[0208] wherein,

[0209] R 1a is H, C 1-4 alkyl, or halo-substituted C 1-4 alkyl;

[0210] t is 0, 1, 2, 3, or 4;

[0211] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitroso, metabolite, prodrug, or mixture thereof.

[0212] In some embodiments, wherein Cy is C 3-8 cycloalkyl, C 2-7 heterocyclyl, C 5-12 spiro bicyclic, C 5-12 spiro heterobicyclic, C 5-12 fused bicyclic, C 5-12 fused heterobicyclic, C 5-12 bridged cyclic, C 5-12 bridged heterocyclic, C 6-10 aryl, or C 1-9 heteroaryl, wherein the Cy is optionally substituted with 1, 2, 3, or 4 R 4 groups.

[0213] In some embodiments, wherein Cy is

[0214]

[0215] wherein,

[0216] X 3 , X 4 , and X 5 are each independently -O-, -S-, -NH-, -(CH2) m1 -NH-(CH2) m2 -, -(CH2) m1 -O-(CH2) m2 -, -(CH2) m1 -S-(CH2) m2 -, or -(CH2) m3 -;

[0217] Each m1 is independently 1, 2, 3 or 4;

[0218] Each m2 is independently 0, 1, 2, 3 or 4;

[0219] Each m3 is independently 1, 2, 3, or 4; and

[0220] n1 can be 0, 1, 2, 3 or 4.

[0221] In some implementation schemes, Cy is

[0222]

[0223] Wherein, Cy is optionally divided by 1, 2, 3 or 4 R 4 replace.

[0224] In some implementation schemes,

[0225] Y is -(L) 1 -W 1 ) m -L 2 -;

[0226] L 1 Does not exist, or L 1 -O-, -C(=O)-, -N(R) i )-、-N(R h C(=O)-, or -S(=O) 0-2 -;

[0227] W 1 C 1-6 Alkylene, the C 1-6 The alkylene group is optionally represented by one, two, three, or four independently selected from H, F, Cl, Br, -OH, -NH2, -NO2, -CN, and C. 1-4 Alkoxy group substitution;

[0228] L 2 Does not exist, or L 2 is -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)-C(=O)-, -C(=O)-C(=O)N(R a )-、-N(R b )-、-C(=O)N(R c )-、-N(R c )C(=O)-、-N(R d )C(=O)N(R c )-、-C(=O)N(R c )-R 15 -C(=O)O-、-C(=O)N(Rc )-R 15 -C(=O)N(R a )-、-N(R g C(=O)O-、-S(=O) 0-2 -、-S(=O) 1-2 N(R e )-、-N(R f S(=O) 1-2 - or -N(R) f S(=O) 1-2 -R 15 -N(R a )-;

[0229] Each R a R b R c R d R e R f R g R h and R i H and C are independent of each other. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 C60 with alkynyl or cyano substitution 1-6 Alkyl, C 1-6 Hydroxyalkyl, halogenated C 1-6 Alkyl, R 16 -C(=O)-, or C 3-6 cycloalkyl C 1-4 alkyl;

[0230] R 15 C 1-6 Alkylene;

[0231] R 16 It is H, C 1-6 Alkyl or halogenated C 1-6 Alkyl groups; and

[0232] m can be 0, 1, or 2.

[0233] In some implementation schemes,

[0234] Y is -(L) 1 -W 1 ) m -L 2 -;

[0235] L 1 Does not exist, or L 1 -O-, -C(=O)-, -N(R) i )-、-N(R h)C(=O)-, or -S(=O) 0-2 -;

[0236] W 1 is C 1-4 alkylene, said C 1-4 alkylene is optionally substituted with 1, 2, 3, or 4 groups independently selected from H, F, Cl, Br, -OH, -NH2, -NO2, -CN, and C 1-4 alkoxy;

[0237] L 2 is absent, or L 2 is -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)-C(=O)-, -C(=O)-C(=O)N(R a )-, -N(R b )-, -C(=O)N(R c )-, -N(R c )C(=O)-, -N(R d )C(=O)N(R c )-, C(=O)N(R c )-R 15 -C(=O)O-, -C(=O)N(R c )-R 15 -C(=O)N(R a )-, -N(R g )C(=O)O-, -S(=O) 0-2 -, -S(=O) 1-2 N(R e )-, -N(R f )S(=O) 1-2 -, or -N(R f )S(=O) 1-2 -R 15 -N(R a )-;

[0238] each R a , R b , R c , R d , R e , R f , R g , R h , and R i is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, halo-substituted C 1-4alkyl, R 16 -C(=O)-, or C 3-6 cycloalkyl C 1-4 alkyl;

[0239] R 15 is H, C 1-6 alkylene;

[0240] R 16 is H, C 1-4 alkyl or haloC 1-4 alkyl; and

[0241] m is 0, 1, or 2.

[0242] In some embodiments, wherein,

[0243] Y is -(L 1 -W 1 ) m -L 2 -;

[0244] L 1 is absent, or L 1 is -O-, -C(=O)-, -N(R i )-, -N(R h )C(=O)-, or -S(=O) 0-2 -;

[0245] W 1 is C 1-4 alkylene, said C 1-4 alkylene is optionally substituted with 1, 2, 3, or 4 groups independently selected from H, F, Cl, Br, -OH, -NH2, -NO2, -CN, and C 1-4 alkoxy;

[0246] L 2 is absent, or L 2 is -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)-C(=O)-, -C(=O)-C(=O)N(R a )-, -N(R b )-, -C(=O)N(R c )-, -N(R c )C(=O)-, -N(R d )C(=O)N(R c )-, -C(=O)N(R c )-R 15 -C(=O)O-, -C(=O)N(R c )-R 15 -C(=O)N(R a)-, -N(R g )C(=O)O-, -S(=O) 0-2 -, 1-2 N(R e )-, -N(R f )S(=O) 1-2 -, f )S(=O) 1-2 -R 15 -N(R a )-;

[0247] each R a , R b , R c , R d , R e , R f , R g , R h and R i are independently H, methyl, ethyl, propyl, CNCH2-, CNCH2CH2-, HOCH2CH2-, -CF3, -CH2CF3, haloC 1-4 alkyl, cyclopropylmethyl, R 16 -C(=O)-, or cyclopropylethyl;

[0248] R 15 is methylene, ethylene, propylene, or butylene;

[0249] R 16 is H, methyl, ethyl, propyl, butyl, -CF3, or CH2CF3 and

[0250] m is 0, 1, or 2.

[0251] In some embodiments, wherein Z is H, -CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, C 3-8 cycloalkyl, C 2-7 heterocyclyl, C 2-7 heterocyclylC 1-4 alkyl, C 3-8 cycloalkylC 1-4 alkyl, C 5-12 spirobicyclyl, C 5-12 spiroheterobicyclyl, C 5-12 fused bicyclyl, C 5-12 fused heterobicyclyl, C 5-12 bridged cyclyl, C 5-12 bridged heterocyclyl, C 6-10 aryl, or C 1-9heteroaryl, wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, C 3-8 cycloalkyl, C 2-7 heterocyclyl, C 5-12 spiro bicyclyl, C 5-12 spiro heterobicyclyl, C 5-12 fused bicyclyl, C 5-12 fused heterobicyclyl, C 5-12 bridged cyclyl, C 5-12 bridged heterocyclyl, C 6-10 aryl and C 1-9 heteroaryl are optionally substituted with one or more R 5 substituents.

[0252] In other embodiments, wherein Z is H, -CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, -C 1-4 alkyl-NR 11 R 11a , or C 3-6 cycloalkyl, or Z is:

[0253]

[0254] wherein X 6 is N, or CH2;

[0255] X 7 is -O-, -S-, -NH-, -(CH2) m4 -NH-(CH2) m5 -, -(CH2) m4 -O-(CH2) m5 -, -(CH2) m4 -S-(CH2) m5 -, or -(CH2) m6 -;

[0256] each m4 is independently 1, 2, 3, or 4;

[0257] each m5 is independently 0, 1, 2, 3, or 4;

[0258] each m6 is independently 1, 2, 3, or 4; and

[0259] n2 is 0, 1, 2, 3, or 4.

[0260] In other embodiments, Z is H, -CN, methyl, ethyl, propyl, t-butyl, -CF3, -CH2CF3, -CH2CH2CN, -CH2CH2OH, or Z is

[0261]

[0262] In some embodiments, wherein,

[0263] each R 2 is independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, C 6-10 arylC 1-6 alkoxyC 1-6 alkyl, C 6-10 aryloxyC 1-6 alkyl, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14-N(R 9a )C(=O)R 9 -R 14 -OC(=O)NR 10 R 10a -R 14 -NR 11 R 11a -R 14 -N(R 12 S(=O) 1-2 R 12a or -R 14 -N(R 13 )C(=O)NR 13a R 13b .

[0264] In other implementation schemes, among which,

[0265] Each R 2 They are independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, and C, respectively. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-4 alkyl and cyano substituted C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, C 6-10 Aryl C 1-4 Alkoxy C 1-4 Alkyl, C 6-10 Aryloxy C 1-4 Alkyl group, -S (=O) 0-2 R 7 -C(=O)R 8 -OS (=O) 1-2 R 7a -OC(=O)R 8a -N(R) 9a )C(=O)R 9 -OC(=O)NR 10 R 10a -NR 11 R 11a -N(R) 12 S(=O) 1-2 R 12a -N(R) 13 )C(=O)NR 13a R 13b -R 14 -S(=O) 0-2 R 7, -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b .

[0266] In other embodiments, wherein,

[0267] each R 2 is independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, methyl, ethyl, propyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, benzyloxymethyl, benzyloxyethyl, phenoxy- methyl, phenoxyethyl, -CH2CH2CN, -CH2CH2OH, -CH2OH, -CF3, -CH2CF3, or -CH2CH2C(=O)NH2.

[0268] In some embodiments, wherein,

[0269] each R 3 is independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, C 1-6 1-6 alkyl, C 2-6 1-6 alkenyl, C 2-6 1-6 alkynyl, halo C 1-6 1-6 alkyl, cyano-substituted C 1-6 1-6 alkyl, C 1-6 1-6 hydroxyalkyl, C 1-6 1-6 alkoxy, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a-N(R 9a )C(=O)R 9 , -N(R 10 )C(=O)OR 10a , -N(R 11 )S(=O) 11a R 12 , -N(R 1-2 )S(=O) 12a 2R 13 , -N(R 13a )S(=O) 13b 2NR 14 , -S(=O) 0-2 R 7 , -S(=O) 14 2R 8 , -S(=O) 14 2NR 1-2 , -OS(=O) 7a 2R 14 , -OC(=O)R 8a , -OC(=O)OR 14 , -N(R 9a )C(=O)R 9 , -N(R 14 )C(=O)OR 10 , -N(R 10a )NR 14 2R 11 , -N(R 11a )NR 14 2C(=O)R 12 , -N(R 1-2 )NR 12a 2C(=O)OR 14 , -N(R 13 )S(=O) 13a 2R 13b .

[0270] In other embodiments, wherein,

[0271] each R 3 is independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a-OC(=O)R 8a -N(R 9a )C(=O)R 9 -OC(=O)NR 10 R 10a -NR 11 R 11a -N(R 12 )S(=O) 1-2 R 12a -N(R 13 )C(=O)NR 13a R 13b -R 14 -S(=O) 0-2 R 7 -R 14 -C(=O)R 8 -R 14 -OS(=O) 1-2 R 7a -R 14 -OC(=O)R 8a -R 14 -N(R 9a )C(=O)R 9 -R 14 -OC(=O)NR 10 R 10a -R 14 -NR 11 R 11a -R 14 -N(R 12 )S(=O) 1-2 R 12a -R 14 -N(R 13 )C(=O)NR 13a R 13b .

[0272] In other embodiments, wherein,

[0273] each R 3 is independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, methyl, ethyl, propyl, butyl, t-butyl, trifluoromethyl, trifluoroethyl, -CH2CH2CN, -CH2CH2OH, -CH2CH2C(=O)NH2, methoxy, ethoxy, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -N(R9a )C(=O)R 9 、 10 R 10a 、 11 R 11a 、 12 )S(=O) 1-2 R 12a 、 13 )C(=O)NR 13a R 13b 、 14 -S(=O) 0-2 R 7 、 14 -C(=O)R 8 、 14 -OS(=O) 1-2 R 7a 、 14 -OC(=O)R 8a 、 14 -N(R 9a )C(=O)R 9 、 14 -OC(=O)NR 10 R 10a 、 14 -NR 11 R 11a 、 14 -N(R 12 )S(=O) 1-2 R 12a 、 14 -N(R 13 )C(=O)NR 13a R 13b 。

[0274] In some embodiments, wherein,

[0275] each R 4 is independently H, oxo (C=O), -CN, -NO2, -OH, -NH2, F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a-C(=O)OR 8a -OC(=O)R 8a -N(R 9a )C(=O)R 9 -C(=O)NR 9a R 9 -OC(=O)NR 10 R 10a -NR 11 R 11a -N(R 12 )S(=O) 1-2 R 12a -N(R 13 )C(=O)NR 13a R 13b -R 14 -S(=O) 0-2 R 7 -R 14 -C(=O)R 8 -R 14 -OS(=O) 1-2 R 7a -R 14 -OC(=O)R 8a -R 14 -N(R 9a )C(=O)R 9 -R 14 -OC(=O)NR 10 R 10a -R 14 -NR 11 R 11a -R 14 -N(R 12 )S(=O) 1-2 R 12a -R 14 -N(R 13 )C(=O)NR 13a R 13b .

[0276] In other embodiments, wherein,

[0277] each R 4 is independently H, oxo (C=O), -CN, -NO2, -OH, -NH2, F, Cl, Br, I, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, halo, -CN, -OR 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -C(=O)OR 8a , -OC(=O)R 8a , -N(R 9a )C(=O)R 9 , -C(=O)NR 9a R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b .

[0278] In other embodiments, wherein,

[0279] each R 4independently H, oxo (C=0), -CN, -N02, -OH, -NH2, F, CI, Br, I, methyl, ethyl, propyl, butyl, t-butyi, trifluoromethyl, trifluoroethyl, -CH2CH2CN, -CH2CH2OH, -CH2OH, -CH2CH2C(=0)NH2, methoxy, ethoxy, -S(=0) 0-2 R 7 , -C(=0)R 8 , -OS(=0) 1-2 R 7a , -C(=0)OR 8a , -OC(=0)R 8a , -N(R 9a )C(=0)R 9 , -C(=0)NR 9a R 9 , -OC(=0)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=0) 1-2 R 12a , -N(R 13 )C(=0)NR 13a R 13b , -R 14 -S(=0) 0-2 R 7 , -R 14 -C(=0)R 8 , -R 14 -OS(=0) 1-2 R 7a , -R 14 -OC(=0)R 8a , -R 14 -N(R 9a )C(=0)R 9 , -R 14 -OC(=0)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=0) 1-2 R 12a , or -R 14 -N(R 13 )C(=0)NR 13a R 13b .

[0280] In some embodiments, wherein,

[0281] each R 5 independently H, oxo (C=0), -CN, -N02, -OH, -NH2, F, CI, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, haloC 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 6-10 aryl, C 6-10 arylC 1-4 alkyl, -S(=0) 0-2 R 7 , -C(=0)R 8 , -OS(=0) 1-2 R 7a , -OC(=0)R 8a , -C(=0)OR 8a , -N(R 9a )C(=0)R 9 , -OC(=0)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=0) 1-2 R 12a , -N(R 13 )C(=0)NR 13a R 13b , -R 14 -S(=0) 0-2 R 7 , -R 14 -C(=0)R 8 , -R 14 -OS(=0) 1-2 R 7a , -R 14 -OC(=0)R 8a , -R 14 -N(R 9a )C(=0)R 9 , -R 14 -OC(=0)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=0) 1-2 R12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b .

[0282] In other embodiments, wherein,

[0283] each R 5 is independently H, oxo (C=O), -CN, -NO2, -OH, -NH2, F, Cl, Br, I, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylamino, haloC 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 6-10 aryl, C 6-10 arylC 1-4 alkyl, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14 -OC(=O)NR10 R 10a , 14 -NR 11 R 11a , 14 -N(R 12 )S(=O) 1-2 R 12a , 14 -N(R 13 )C(=O)NR 13a R 13b .

[0284] In other embodiments, wherein,

[0285] each R 5 is independently H, oxo (C=O), -CN, -NO2, -OH, -NH2, F, Cl, Br, I, methyl, ethyl, propyl, butyl, t-butyl, trifluoromethyl, trifluoroethyl, -CH2CH2CN, -CH2CH2OH, -CH2CH2C(=O)NH2, methoxy, ethoxy, phenyl, benzyl, phenethyl, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -C(=O)OR 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R 9 , -R 14-OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b .

[0286] In some embodiments, wherein,

[0287] each R 6 is independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R 9a )C(=O)R9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b .

[0288] In other embodiments, wherein,

[0289] each R 6 is independently H, -CN, -NO2, -OH, -NH2, F, Cl, Br, I, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, haloC 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, -S(=O) 0-2 R 7 , -C(=O)R 8 , -OS(=O) 1-2 R 7a , -OC(=O)R 8a , -N(R 9a )C(=O)R 9 , -OC(=O)NR 10 R 10a , -NR 11 R 11a , -N(R 12 )S(=O) 1-2 R 12a , -N(R 13 )C(=O)NR 13a R 13b , -R 14 -S(=O) 0-2 R 7 , -R 14 -C(=O)R 8 , -R 14 -OS(=O) 1-2 R 7a , -R 14 -OC(=O)R 8a , -R 14 -N(R9a )C(=O)R 9 , -R 14 -OC(=O)NR 10 R 10a , -R 14 -NR 11 R 11a , -R 14 -N(R 12 )S(=O) 1-2 R 12a , or -R 14 -N(R 13 )C(=O)NR 13a R 13b .

[0290] In other embodiments, wherein,

[0291] each R 6 is independently H, -CN, F, Cl, Br, I, methyl, ethyl, propyl, t-butyl, methoxy, ethoxy, -OCH2CF3, -CF3, -CH2CF3, -CH2CH2CN, -CH2CH2OH, -C(=O)CH3, -C(=O)CF3, -C(=O)OCH3, -C(=O)NH2, or -NHC(=O)CH3.

[0292] In some embodiments, wherein,

[0293] each R 7 , R 7a , R 8 , R 8a , R 9 , and R 12a is independently H, C 1-6 1-6 alkyl, halo C 1-6 1-6 alkyl, cyano substituted C 1-6 1-6 alkyl, C 2-6 2-6 alkenyl, C 2-6 2-6 alkynyl, C 6-10 6 aryl, C 6-10 6 aryl C 1-6 1-6 alkyl, C 1-9 2-6 heteroaryl, C 1-9 2-6 heteroaryl C 1-6 1-6 alkyl, C 3-8 3-6 cycloalkyl, C 3-8 3-6 cycloalkyl C 1-6 1-6 alkyl, C 2-9 2-6 heterocyclyl, or C 2-9 2-6 heterocyclyl C 1-6 1-6 alkyl;

[0294] each R 9a , R 10 , and R10a H and C are independent of each other. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 C-type substituted with alkynyl or cyano groups 1-6 Alkyl or halogenated C 1-6 alkyl;

[0295] Each R 11 and R 10a H and C are independent of each other. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl and cyano substituted C 1-6 Alkyl, or C 6-10 Aryl C 1-6 alkyl;

[0296] Each R 12 R 13 R 13a and R 13b H and C are independent of each other. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 C-type substituted with alkynyl or cyano groups 1-6 Alkyl or halogenated C 1-6 Alkyl groups; and

[0297] Each R 14 C, each independently 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl and cyano-substituted C 1-6 Alkylene or halogenated C 1-6 Alkylene.

[0298] In other implementation schemes, among which,

[0299] Each R 7 R 7a R 8 R 8a R 9 and R 12a H and C are independent of each other. 1-4 Alkyl, Halogenated C 1-4 alkyl and cyano substituted C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 6-10 Aryl, C 6-10 Aryl C 1-4 Alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1-4 Alkyl, C3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, C 2-7 heterocyclyl, or C 2-7 heterocyclyl C 1-4 alkyl;

[0300] each R 9a , R 10 , and R 10a is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano-substituted C 1-4 alkyl, or halo C 1-4 alkyl;

[0301] each R 11 , and R 10a is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, cyano-substituted C 1-4 alkyl, or C 6-10 aryl C 1-4 alkyl;

[0302] each R 12 , R 13 , R 13a , and R 13b is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano-substituted C 1-4 alkyl, or halo C 1-4 alkyl; and

[0303] each R 14 is independently C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, cyano-substituted C 1-4 alkylene, or halo C 1-4 alkylene.

[0304] In other embodiments, wherein,

[0305] each R 7 , R 7a , R 8 , R 8a , R 9 , and R 12aeach R is independently H, methyl, ethyl, propyl, t-butyl, -CF3, -CH2CF3, -CH2CH2CN, -CH2CH2OH, vinyl, propenyl, ethynyl, phenyl, benzyl, phenethyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, C 2-7 heterocyclyl, or C 2-7 heterocyclyl C 1-4 alkyl;

[0306] each R 9a , R 10 , and R 10a is independently H, methyl, ethyl, propyl, t-butyl, -CF3, -CH2CF3, -CH2CH2CN, vinyl, propenyl, or ethynyl;

[0307] each R 11 and R 10a is independently H, methyl, ethyl, propyl, t-butyl, -CF3, -CH2CF3, -CH2CH2CN, vinyl, propenyl, ethynyl, benzyl, or phenethyl;

[0308] each R 12 , R 13 , R 13a and R 13b is independently H, methyl, ethyl, propyl, t-butyl, -CF3, -CH2CF3, -CH2CH2CN, vinyl, propenyl, or ethynyl; and

[0309] each R 14 is independently methylene, ethylene, propylene, butylene, vinylene, propenylene, acetylene, -CH2CH(CN)-, or -CH2CH(F)-.

[0310] In some embodiments, the compound has the structure of any one of Formulas (Id)-(Ig):

[0311]

[0312] wherein,

[0313] R 1a is H, methyl, ethyl, propyl, -CF3, or -CH2CF3;

[0314] R 2 and R 3each independently H, -CN, F, Cl, Br, methyl, ethyl, propyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, benzyloxymethyl, benzyloxyethyl, -CF3, -CH2CF3, -CH2CH2CN, -CH2CH2OH, or -CH2CH2C(=O)NH2;

[0315] R 4 is H, oxo (=O), -CN, F, Cl, Br, I, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, -OCH2CF3, -CF3, -CH2CF3, -CH2CH2CN, -CH2CH2OH, -CH2OH, -C(=O)CH3, -C(=O)CF3, -C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHCH2CH3, or -NHC(=O)CH3;

[0316] R 6 is H, -CN, F, Cl, Br, I, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, -OCH2CF3, -CF3, -CH2CF3, -CH2CH2CN, -CH2CH2OH, -C(=O)CH3, -C(=O)CF3, -C(=O)OCH3, -C(=O)NH2, or -NHC(=O)CH3;

[0317] X 3 is N or CH;

[0318] L 1 is absent, or L 1 is -O-, -C(=O)-, -N(R i )-, -N(R h )C(=O)-, or -S(=O) 0-2 -;

[0319] W 1 is a C 1-4 alkylene group, which C 1-4 alkylene group is optionally substituted with 1, 2, 3, or 4 groups independently selected from H, F, Cl, Br, -OH, -NH2, -NO2, -CN, and C 1-4 alkoxy;

[0320] R h and R i each independently H, methyl, ethyl, propyl, tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, haloC1-4 alkyl, cyclopropylmethyl, HC(=0)-, CH3C(=0)-, or cyclopropylethyl;

[0321] m1 is 1, 2, 3, or 4;

[0322] n1 is 0, 1, 2, 3, or 4; and

[0323] Z has the definition described herein;

[0324] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitroso, metabolite, prodrug, or mixture thereof.

[0325] In some embodiments, the compound of the present application is a compound having one of the following structures:

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitroso, metabolite, prodrug, or mixture thereof.

[0339] In another aspect, the present application provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitroso, metabolite, prodrug thereof, and a pharmaceutically acceptable excipient, diluent, or carrier.

[0340] In some embodiments, the pharmaceutical composition described herein further comprises an additional therapeutic agent.

[0341] In some embodiments, the composition described herein, wherein the additional therapeutic agent is a therapeutic agent for a fibrotic disease, a proliferative disease, an inflammatory disease, an autoimmune disease, a respiratory disease, a cardiovascular disease, a neurodegenerative disease, a dermatological disorder, and / or a disease associated with abnormal angiogenesis.

[0342] In some embodiments, the pharmaceutical composition described herein, wherein the additional therapeutic agent includes, but is not limited to, an immunomodulatory agent, an analgesic agent, a non-steroidal anti-inflammatory drug, a steroid, a synthetic DMARD, an agent for treating a proliferative disease, a glucocorticoid, a cytostatic agent, an alkylating agent, an antimetabolite, a cytotoxic antibiotic, an antibody, and the like.

[0343] In another aspect, the present application provides a use of a compound described herein or a pharmaceutical composition described herein for the preparation of a medicament for preventing or treating a disease having an increased expression of ATX as a pathological characteristic in a mammal.

[0344] In some embodiments, the disease having an increased expression of ATX as a pathological characteristic includes a cancer, a fibrotic disease, a metabolic disease, a myelodysplastic syndrome, a cardiovascular disease, an autoimmune disease, inflammation, a nervous system disease, or pain.

[0345] In some embodiments, the disease having an increased expression of ATX as a pathological characteristic is idiopathic pulmonary fibrosis or liver fibrosis. In some embodiments, the compound of the present application or a pharmaceutical composition thereof can be administered in combination with an additional therapeutic agent.

[0346] In some embodiments, the use described herein includes administering to the mammal an amount of a compound or a pharmaceutical composition described herein sufficient to achieve the treatment or prevention.

[0347] Pharmaceutical compositions, formulations, and uses

[0348] When used as a medicament, the compounds of the present application are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one compound described herein according to Formula I, la, lb, Ic, Id, Ie, If, or Ig. Generally, the compounds of the present application are administered in a pharmaceutically effective amount. The amount of a compound of the present application actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the present application administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0349] The pharmaceutical compositions of the present application can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intraarticular, intravenous, intramuscular, and intranasal. Depending on the intended delivery route, the compounds of the present application are preferably formulated as injectable or oral compositions or as a salve, as a lotion, or as a patch (all for transdermal administration).

[0350] In certain embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein or other prophylactic or therapeutic agent) and typically one or more pharmaceutically acceptable carriers or excipients. In specific embodiments and the present application, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” includes a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic agent is administered. Such a pharmaceutical carrier can be a sterile liquid, such as water and oils, including those of

[0351] Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, in certain embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors, including, but not limited to, the way the dosage form will be administered to a subject and the particular active ingredients in the dosage form. If desired, the composition or single unit dosage form can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0352] Orally administered compositions can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage form to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable for unitary dosing to human individuals and other mammals each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with suitable pharmaceutical excipients, vehicles, or carriers, etc. Typical unit dosage forms include pre-filled, pre-measured ampules or syringes of liquid compositions or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions the present compounds of Formula I, Ia, Ib, Ic, Id, Ie, If, or Ig are typically secondary components (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight) with the remainder being various excipients, vehicles and processing aids which facilitate the formation of the desired administration form.

[0353] In another aspect, the present application provides a compound of the present application or a pharmaceutical composition comprising a compound of the present application for use in medicine. In particular embodiments, the present application provides a compound of the present application or a pharmaceutical composition comprising a compound of the present application for use in the prevention and / or treatment of a fibrotic disease, a proliferative disease, an inflammatory disease, an autoimmune disease, a respiratory disease, a cardiovascular disease, a neurodegenerative disease, a dermatological disorder, and / or a disease associated with abnormal angiogenesis.

[0354] In some embodiments, the present application provides a compound of the present application or a pharmaceutical composition comprising a compound of the present application for use in the preparation of a medicament for the prevention and / or treatment of a fibrotic disease, a proliferative disease, an inflammatory disease, an autoimmune disease, a respiratory disease, a cardiovascular disease, a neurodegenerative disease, a dermatological disorder, and / or a disease associated with abnormal angiogenesis.

[0355] In some embodiments, the present application provides a pharmaceutical composition comprising a compound of the present application and another therapeutic agent. In particular embodiments, the other therapeutic agent is a therapeutic agent for a fibrotic disease, a proliferative disease, an inflammatory disease, an autoimmune disease, a respiratory disease, a cardiovascular disease, a neurodegenerative disease, a dermatological disorder, and / or a disease associated with abnormal angiogenesis.

[0356] In another method of treatment, the present application provides a method of preventing and / or treating a mammal having a fibrotic disease, a proliferative disease, an inflammatory disease, an autoimmune disease, a respiratory disease, a cardiovascular disease, a neurodegenerative disease, a dermatological disorder, and / or a disease associated with abnormal angiogenesis, comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions described herein for the treatment or prevention of the condition.

[0357] In other embodiments, the present application provides the use of a compound of the present application or a pharmaceutical composition comprising a compound of the present application for the manufacture of a medicament for the prevention and / or treatment of a fibrotic disease. In particular embodiments, the fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseases of varying etiologies (including iatrogenic drug-induced fibrosis, occupational and / or environmental induced fibrosis), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleimyomatosis, genetic diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin-induced pulmonary fibrosis, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), renal fibrosis, tubulointerstitial fibrosis, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, Alport, intestinal fibrosis, liver fibrosis, cirrhosis, alcohol-induced liver fibrosis, toxin / drug-induced liver fibrosis, hemochromatosis, non-alcoholic steatohepatitis (NASH), biliary duct injury, primary biliary cirrhosis, infection-induced liver fibrosis, virus-induced liver fibrosis and autoimmune hepatitis, corneal scarring, hypertrophic scarring, Dupuytren's disease, keloids, skin fibrosis, cutaneous scleroderma, systemic sclerosis, spinal cord injury / fibrosis, bone marrow fibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, Peyronie's disease, or chronic lymphocytic. More particularly, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0358] A particular embodiment of the method of the present application comprises administering to an individual having a fibrotic disease an effective amount of a compound of the present application of Formula I, Ia, Ib, Ic, Id, Ie, If, or Ig for a period of time sufficient to reduce the level of fibrosis in the individual and, preferably, to terminate the process causing the fibrosis. A specific embodiment of the method comprises administering to an individual patient having idiopathic pulmonary fibrosis an effective amount of a compound of the present application of Formula I, Ia, Ib, Ic, Id, Ie, If, or Ig for a period of time sufficient to reduce or prevent idiopathic pulmonary fibrosis in the patient and, preferably, to terminate the process causing the idiopathic pulmonary fibrosis.

[0359] Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for about 1 to about 120 hours, especially 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more can also be administered to achieve appropriate steady state levels. It is not expected that the maximum total dose for a 40 to 80 kg human patient will exceed about 1 g / day.

[0360] For the prevention and / or treatment of long-term conditions (e.g., degenerative conditions), treatment regimens are typically extended over many months or many years, and thus oral administration is preferred for patient convenience and tolerability. In the case of oral administration, a regimen of one to four (1-4) conventional doses per day, especially one to three (1-3) conventional doses per day, often one to two (1-2) conventional doses per day, and most often one (1) conventional dose per day is a representative regimen. Alternatively, for drugs with long-lasting effects, once every other week, once a week, and once a day are representative regimens in the case of oral administration. In particular, the dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.

[0361] Using these modes of administration, each dose provides from about 1 to about 1000 mg of a compound of the application, with each individual dose providing from about 10 to about 500 mg, preferably from about 30 to about 250 mg.

[0362] In the case of prophylactic administration to prevent the onset of a condition, a compound of the application will generally be administered to a patient at risk of developing the condition at the above-described dosage levels, under the advice and supervision of a physician. Patients at risk of developing a particular condition generally include patients having a family history of the condition or patients who have been identified through genetic testing or screening as being particularly susceptible to developing the condition.

[0363] A compound of the application can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compounds of the application that exhibit the same or similar therapeutic activities and that are determined to be safe and effective for the combined administration. In particular embodiments, the co-administration of two (or more) active agents allows for a significant reduction in the dose of each active agent used, thereby reducing the side effects that can be seen.

[0364] In some embodiments, a compound of the application or a pharmaceutical composition comprising a compound of the application is administered as a medicament. In particular embodiments, the pharmaceutical composition further comprises an additional active ingredient.

[0365] In some embodiments, the compounds of the application are co-administered with additional therapeutic agents for the treatment and / or prevention of diseases involving inflammation, particular active agents include, but are not limited to, immunomodulators such as azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen and piroxicam.

[0366] In some embodiments, the compounds of the application are co-administered with additional therapeutic agents for the treatment and / or prevention of arthritis (e.g. rheumatoid arthritis), particular active agents include, but are not limited to, analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, synthetic DMARDS (such as, but not limited to, methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib and cyclosporin) and biological DMARDS (such as, but not limited to, infliximab, etanercept, adalimumab, rituximab and abatacept).

[0367] In some embodiments, the compounds of the application are co-administered with additional therapeutic agents for the treatment and / or prevention of proliferative disorders, particular active agents include, but are not limited to, methotrexate, leukovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibodies (e.g., Herceptin TM ), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g., Iressa, Tarceva, Erbitux), VEGF inhibitors (e.g., Avastin), proteasome inhibitors (e.g., Velcade), Gleevec, and hsp90 inhibitors (e.g., 17-AAG). In addition, the compounds of the application of Formula I, Ia, Ib, Ic, Id, or Ie can be administered in combination with other therapies including, but not limited to, radiation therapy or surgery. In particular embodiments, the proliferative disorder is selected from a cancer, a myeloproliferative disease, or a leukemia.

[0368] In some embodiments, the compounds of the application are co-administered with additional therapeutic agents for the treatment and / or prevention of autoimmune diseases, particular active agents include, but are not limited to, glucocorticoids, cytostatic agents (e.g., purine analogs), alkylating agents (e.g., nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds of the application, and others), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., dactinomycin, anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies, and ), cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g., IFN-β), TNF binding proteins (e.g., infliximab, etanercept, or adalimumab), mycophenolate, fingolimod, and myriocin.

[0369] As will be apparent to those skilled in the art, co-administration includes any means of delivering two or more therapeutic agents to a patient as part of the same therapeutic regimen. While the two or more active agents can be administered simultaneously in a single formulation (i.e., as a single pharmaceutical composition), this is not necessary. The active agents can also be administered in different formulations, at different times. DETAILED DESCRIPTION

[0370] In order to describe the application, the following examples are included. It is to be understood that the application is not limited to these examples, which are provided merely for purposes of illustration.

[0371] In general, the compounds of the application can be prepared by the methods described herein, unless otherwise specified, where the substituents are as defined in Formula I, Ia, Ib, Ic, Id, Ie, If, or Ig. The following reaction schemes and examples are intended to further illustrate the application.

[0372] Those skilled in the art will appreciate that the chemical reactions described herein can be performed by using conventional techniques, which are well known to those skilled in the art. It will also be appreciated that, where appropriate, the chemical reactions can be performed at temperatures and / or pressures in either or both of the liquid or vapor phase. The compounds of the application can be prepared in a number of ways based on the teachings of this specification, as will be apparent to one skilled in the art. Due to the inherent variability of chemical reactions, the yields of the processes described in this specification, and of the intermediates and final products they produce, can vary. It will be appreciated that, in some instances, optimisation of reaction conditions, including choice of solvent, reaction temperature, etc., can be necessary in order to achieve the best possible yield.

[0373] Unless otherwise indicated, all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and used without further purification, unless otherwise indicated. General reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoguyu Chemicals Co., Ltd., Tianjin Fumian Chemical Reagent Factory, Wuhan Xinhua Yuan Science and Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haoyang Chemical Factory.

[0374] Anhydrous tetrahydrofuran, dioxane, toluene, diethyl ether were dried over sodium metal. Anhydrous dichloromethane and chloroform were dried over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were used as received.

[0375] The following reactions were generally carried out under a positive pressure of nitrogen or argon or in a dry box, reaction vessels were fitted with a suitable rubber septum and substrates were introduced via syringe. Glassware was oven (120°C) or flame dried where necessary.

[0376] Chromatography was performed using silica gel. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.

[0377] 1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer. 1 H NMR spectra were recorded in CDC13, DMSO-d6, CD3OD or acetone-d6 as solvent (in ppm) with TMS (0 ppm) or chloroform (7.26 ppm) as reference standard. When multiplets occur, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0378] Low resolution mass spectrometry (MS) data were measured on an Agilent 6120 quadrupole HPLC-MS (column type: Zorbax SB-C18, 2.1 x 30 mm, 3.5 micron, 6 min, flow rate 0.6 mL / min. Mobile phase: 5% - 95% (CH3CN with 0.1% formic acid) in (H2O with 0.1% formic acid), electrospray ionization (ESI), UV detection at 210 nm / 254 nm.

[0379] Pure compounds were measured on an Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column type: NOVASEP 50 / 80 mm DAC), UV detection at 210 nm / 254 nm.

[0380] The following abbreviations are used throughout the application:

[0381] CD3OD deuterated methanol

[0382] CDC13 deuterated chloroform

[0383] DMF N,N-dimethylformamide

[0384] DMSO-d6 deuterated dimethyl sulfoxide

[0385] g gram

[0386] h hour

[0387] mL, ml milliliter

[0388] RT, rt, r.t. room temperature

[0389] Boc tert-butyloxycarbonyl

[0390] Cbz carbobenzyloxy

[0391] PMB p-methoxybenzyl

[0392] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium

[0393] JohnPhos 2-(di-tert-butylphosphino)biphenyl

[0394] Typical synthetic procedures for the preparation of the compounds disclosed in the present application are shown in the following synthesis schemes 1, 2 and 3.

[0395] Synthesis scheme 1:

[0396]

[0397] wherein E 1 , E 2 is selected from CI, Br or I; E 3 is selected from CI, Br, I, OMs, OTs or OTf; Pr 1 is selected from Boc, Cbz or PMB; Z, Y, Cy, Ar 1 , Ar 2 , W, Ar 3 , and R 1 all have the definitions as described in the present application.

[0398] intermediate 1-3; then intermediate 1-3 is reacted with a strong base (such as sodium hydride, potassium tert-butoxide or sodium tert-butoxide) first, and then reacted with intermediate 1-4 by nucleophilic substitution to obtain intermediate 1-5; the obtained intermediate 1-5 can be deprotected under acidic conditions (such as trifluoroacetic acid, hydrogen chloride), or palladium catalytic hydrogenation, or reacted with trimethylsilyl iodide to remove the protecting group Pr 1 to obtain intermediate 1-6; intermediate 1-6 and intermediate 1-7 are reacted by nucleophilic substitution in the presence of a base (such as triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate) and under heating conditions (25°C to 120°C) to obtain the compound represented by formula I.

[0399] Synthetic scheme 2:

[0400]

[0401] wherein, E 1 and E 2 are each independently selected from Cl, Br or I; E 3 is selected from Cl, Br, I, OMs, OTs or OTf; Pr 2 is selected from tert-butyl or 2,4,4-trimethylpentan-2-yl; Pr 1 , Z, Y, Cy, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , R 1a , R 2 , R 6 , and t all have the definitions described in the present application.

[0402] intermediate 2-1 and Pr 2 NC and aldehyde R 2 CHO are reacted by a three-component reaction in the presence of a Lewis acid (such as magnesium chloride) to obtain intermediate 2-2; intermediate 2-2 is reacted by heating in formic acid to obtain intermediate 2-3; the obtained intermediate 2-3 and intermediate 1-2 are reacted by nucleophilic substitution in the presence of a base (such as triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate, potassium tert-butoxide or sodium tert-butoxide) and under heating conditions (50°C to 150°C) to obtain intermediate 2-4; intermediate 2-4 is first reacted with a strong base (such as sodium hydride, potassium tert-butoxide or sodium tert-butoxide), and then reacted with intermediate 2-5 by nucleophilic substitution, and then reacted with substituted alkyl R 1a E 4The reaction gives intermediate 2-6; intermediate 2-6 can be deprotected under acidic conditions (such as trifluoroacetic acid, hydrogen chloride) or palladium catalyzed hydrogenation or reaction with trimethylsilyl iodide 1 to give intermediate 2-7; intermediate 2-7 and intermediate 1-7 are reacted by nucleophilic substitution under basic conditions (such as triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate) and heating (25 °C to 120 °C) to give a compound of formula If.

[0403] Synthesis scheme 3:

[0404]

[0405] wherein Pr 2 is selected from tert-butyl or 2,4,4-trimethylpentan-2-yl; Pr 1 , Cy, X 2 , Y 3 , and R 2 all have the definitions described in the present application.

[0406] intermediate 3-1 and Pr 2 NC and aldehyde R 2 CHO are reacted by a three-component reaction catalyzed by a Lewis acid (such as magnesium chloride) to give intermediate 3-2; the obtained intermediate 3-2 is reacted by heating in formic acid to give intermediate 2-4.

[0407] Examples

[0408] Example 1

[0409] Preparation of 2-{[6-ethyl-2-(4-(methylsulfonyl)piperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0410]

[0411] Step 1): 2-bromo-6-ethyl-N-(2,4,5-trimethylpentan-2-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-amine

[0412] To a solution of 2-amino-5-bromo-l,3,4-thiadiazole (2.0 g, 11.2 mmol) in n-butanol (20 mL) was added l,l,3,3-tetramethylbutyl isocyanide (1.56 g, 11.2 mmol), n-propionaldehyde (1.6 g, 28 mmol) and anhydrous magnesium chloride (0.5 g, 5.6 mmol) and the reaction was stirred at 120 °C for 4 h. The solvent was evaporated. Purification by column chromatography (ethyl acetate: petroleum ether = 1:2) gave 3.5 g of brown oil. Yield: 88%. MS (m / z): 359.1 [M+1], 361.1 [M+1].

[0413] Step 2) N-(2-bromo-6-ethylimidazo[2,l-b][l,3,4]thiadiazol-5-yl)formamide

[0414] To a solution of 2-bromo-6-ethyl-N-(2,4,5-trimethylpentan-2-yl)imidazo[2,l- b][l,3,4]thiadiazol-5-amine (3.5 g, 9.75 mmol) in formic acid (20 mL) was stirred at 80 °C for 3 h. The solvent was evaporated. The product was obtained as a light brown foam by trituration with petroleum ether, filtration and drying. Yield: 2.3 g, 74%. MS (m / z): 275.0 [M+1], 277.0 [M+1].

[0415] Step 3) 4-(6-ethyl-5-formamidimidazo[2,l-b][l,3,4]thiadiazol-2-yl)piperazine-l- carboxylic acid tert-butyl ester

[0416] To a solution of N-(2-bromo-6-ethylimidazo[2,l-b][l,3,4]thiadiazol-5-yl)formamide (300 mg, 1.1 mmol) and piperazine-l-carboxylic acid tert-butyl ester (305 mg, 1.64 mmol) in DMF (5 mL) was added potassium carbonate (304 mg, 2.2 mmol) and the reaction was stirred at 75 °C for 2 h. The reaction was cooled and poured into water and extracted with ethyl acetate (20 mL x 2). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, evaporated and purified by column chromatography (dichloromethane:methanol = 40: 1) to give 200 mg of light brown foam. Yield: 48%. MS (m / z): 381.3 [M+1].

[0417] Step 4) 4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,l-b][l,3,4]thiadiazol-2-yl}piperazine-l-carboxylic acid tert-butyl ester

[0418] tert-Butyl 4-(6-ethyl-5-formamidylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazine-1- carboxylate (330 mg, 0.87 mmol) was dissolved in tetrahydrofuran (8 mL), sodium hydride (87 mg, 2.18 mmol) was added, stirred at room temperature for 30 minutes, then 2-chloro-4-(4-fluorophenyl)thiazole-5-carbonitrile (176 mg, 0.74 mmol) was added, heated at 70 °C for half an hour, then cooled to room temperature, iodomethane (108 μL, 1.74 mmol) was added, reacted at 65 °C for another half an hour. After cooling, the reaction solution was poured into water, extracted with ethyl acetate (15 mL x 2), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography to give the product 350 mg, yield: 84%. MS (m / z): 569.3 [M+1].

[0419] Step 5) Preparation of 2-{[6-ethyl-2-(piperazin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0420] tert-Butyl 4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}piperazine-1-carboxylate (150 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and reacted at room temperature for 2 hours. After rotary evaporation, dichloromethane was added, the pH was adjusted to about 8 with a saturated sodium bicarbonate solution, extracted with dichloromethane (15 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give a foamy solid 112 mg, yield: 91%. MS (m / z): 469.2 [M+1].

[0421] Step 6) 2-{[6-ethyl-2-(4-(methylsulfonyl)piperazin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0422] 2-{[6-ethyl-2-(piperazin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile (40 mg, 0.085 mol) was dissolved in dichloromethane (2 mL), triethylamine (22 μL, 0.16 mmol) and methanesulfonyl chloride (13 μL, 0.16 mmol) were added. After reaction at room temperature for 1 hour, rotary evaporation was performed, and purification by a preparative plate gave a light yellow solid 29 mg, yield: 63%. 1H NMR (400 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 3.58 (m, 7H), 3.38 (m, 4H), 2.84 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H).

[0423] Example 2

[0424] Preparation of 2-{[6-ethyl-2-(4-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-7-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0425]

[0426] Preparation of 2-{[6-ethyl-2-(4-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-7-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile 1 H NMR (400 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 3.58 (m, 7H), 3.38 (m, 4H), 2.84 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H).

[0427] Example 3

[0428] Preparation of 2-{[6-ethyl-2-(4-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-7-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0429]

[0430] 2-{[6-ethyl-2-(2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,7-diazaspiro[3.5]nonan-7-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared according to the procedure described in Reference Example 2, using tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate instead of tert-butyl piperazine-1-carboxylate. 1 H NMR (500 MHz, CDC13) δ: 8.15 (m, 2H), 7.16 (m, 2H), 3.73 (m, 4H), 3.57 (s, 7H), 3.41 (m, 4H), 2.88 (s, 3H), 2.59 (q, J = 7.5 Hz, 2H), 1.93 (m, 4H), 1.28 (t, J = 7.5 Hz, 3H).

[0431] Example 4

[0432] 2-{[6-ethyl-2-(2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,7-diazaspiro[3.5]nonan-7-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared according to the procedure described in Reference Example 2, using tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate instead of tert-butyl piperazine-1-carboxylate.

[0433]

[0434] 2-{[6-ethyl-2-(2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,7-diazaspiro[3.5]nonan-7-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared according to the procedure described in Reference Example 2, using tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate instead of tert-butyl piperazine-1-carboxylate. 1 H NMR (500 MHz, CDC13) δ: 8.15 (m, 2H), 7.16 (m, 2H), 3.73 (m, 4H), 3.57 (s, 7H), 3.41 (m, 4H), 2.88 (s, 3H), 2.59 (q, J = 7.5 Hz, 2H), 1.93 (m, 4H), 1.28 (t, J = 7.5 Hz, 3H).

[0435] Example 5

[0436] 2-{[6-ethyl-2-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile

[0437]

[0438] 2-{[6-ethyl-2-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile was prepared according to Reference Example 1, replacing piperazine-1- carboxylic acid tert-butyl ester hemi-hydrogen oxalate with tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate hemi-hydrogen oxalate. 1 H NMR (500 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 4.24 (s, 4H), 4.12 (s, 4H), 3.57 (s, 3H), 2.88 (s, 3H), 2.59 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H).

[0439] Example 6

[0440] 2-{[6-ethyl-2-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile

[0441]

[0442] 2-{[6-ethyl-2-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile was prepared according to Reference Example 2, replacing piperazine-1- carboxylic acid tert-butyl ester hemi-hydrogen oxalate with tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate hemi-hydrogen oxalate. 1H NMR (400 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 4.68 (m, 1H), 4.33 (m, 1H), 4.25 (m, 1H), 4.18 (s, 4H), 3.99 (m, 1H), 3.87 (m, 1H), 3.57 (s, 3H), 3.54 (s, 4H), 3.08 (s, 2H), 2.58 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5 Hz, 3H).

[0443] Example 7

[0444] Preparation of 4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}piperazine-1-carboxamide

[0445]

[0446] To 2-{[6-ethyl-2-(piperazin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4- (4-fluorophenyl)thiazole-5-carbonitrile (40 mg, 0.085 mmol) in dichloromethane (2 mL) was added triethylamine (50 μL, 0.36 mmol) under nitrogen protection, and then trimethylsilyl isocyanate (30 mg, 0.26 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Water (0.5 mL) was added, and the mixture was stirred for 20 minutes. The solvent was evaporated, and the residue was purified by preparative plate (dichloromethane:methanol = 20:1) to give 18 mg of white solid. Yield: 39%. 1 H NMR (400 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 4.55 (s, 2H), 3.58 (m, 7H), 3.48 (m, 4H), 2.59 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H).

[0447] Example 8

[0448] Preparation of 7-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-2,7-diazaspiro[3.5]nonane-2-carboxamide

[0449]

[0450] Referring to Example 7, 7-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-2,7-diazaspiro[3.5]nonane-2-carboxamide was prepared using tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate instead of tert-butyl piperazine-1-carboxylate. 1 H NMR (400 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 4.32 (s, 2H), 3.75 (s, 4H), 3.57 (s, 3H), 3.42 (m, 4H), 2.59 (q, J = 7.6 Hz, 2H), 1.91 (m, 4H), 1.27 (t, J = 7.6 Hz, 3H).

[0451] Example 9

[0452] Preparation of 6-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-2,6-diazaspiro[3.3]heptane-2-carboxamide

[0453]

[0454] Referring to Example 7, 6-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-2,6-diazaspiro[3.3]heptane-2-carboxamide was prepared using tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemi-hydrogenoxalate instead of tert-butyl piperazine-1-carboxylate. 1 H NMR (400 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 4.32 (s, 2H), 3.75 (s, 4H), 3.57 (s, 3H), 3.42 (m, 4H), 2.59 (q, J = 7.6 Hz, 2H), 1.91 (m, 4H), 1.27 (t, J = 7.6 Hz, 3H).

[0455] Example 10

[0456] Preparation of N-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]pyrrolidin-3-yl}-N-methylmethanesulfonamide

[0457]

[0458] N-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]pyrrolidin-3-yl}-N-methylmethanesulfonamide was prepared according to the procedure of Reference Example 1 using 3-tert-butoxy carbamoyl pyrrolidine in place of tert-butyl piperazine-1-carboxylate. 1 HNMR (400 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 4.73 (m, 1H), 3.68 (m, 2H), 3.58 (s, 3H), 3.46 (m, 2H), 2.89 (m, 6H), 2.61 (m, 2H), 2.28 (m, 2H), 1.27 (m, 3H).

[0459] Example 11

[0460] Preparation of 2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)(methyl)amino)pyrrolidin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0461]

[0462] 2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)(methyl)amino)pyrrolidin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared according to the procedure of Reference Example 2 using 3-tert-butoxy carbamoyl pyrrolidine in place of tert-butyl piperazine-1-carboxylate. 1 H NMR (400 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 4.73 (m, 1H), 3.68 (m, 2H), 3.58 (s, 3H), 3.46 (m, 2H), 2.89 (m, 6H), 2.61 (m, 2H), 2.28 (m, 2H), 1.27 (m, 3H).

[0463] Example 12

[0464] Preparation of 1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]pyrrolidin-3-yl}-1-methylurea

[0465]

[0466] Referring to Example 7, 3-tert-butoxycarbonylpyrrolidine is used instead of tert-butyl piperazine-1-carboxylate to prepare 1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2- yl)(methyl)amino)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]pyrrolidin-3-yl}-1- methylurea. 1 H NMR (500 MHz, CDC13) δ: 8.14 (m, 2H), 7.15 (m, 2H), 5.19 (m, 1H), 4.54 (s, 2H), 3.68-3.58 (m, 5H), 3.45 (m, 1H), 3.33 (m, 1H), 2.85 (s, 3H), 2.59 (q, J = 7.5 Hz, 2H), 2.25 (m, 1H), 2.13 (m, 1H), 1.28 (t, J = 7.6 Hz, 3H).

[0467] Example 13

[0468] Preparation of N-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]piperidin-3-yl}-N-methylmethanesulfonamide

[0469]

[0470] Referring to Example 1, 3-tert-butoxycarbonylpiperidine is used instead of tert-butyl piperazine-1-carboxylate to prepare N-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2- yl)(methyl)amino)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]piperidin-3-yl}-N- methylmethanesulfonamide. 1 H NMR (500 MHz, CDC13) δ: 8.14 (m, 2H), 7.15 (m, 2H), 5.19 (m, 1H), 4.54 (s, 2H), 3.68-3.58 (m, 5H), 3.45 (m, 1H), 3.33 (m, 1H), 2.85 (s, 3H), 2.59 (q, J = 7.5 Hz, 2H), 2.25 (m, 1H), 2.13 (m, 1H), 1.28 (t, J = 7.6 Hz, 3H).

[0471] Example 14

[0472] 2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)(methyl)amino)piperidin-l- yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile

[0473]

[0474] Reference Example 2 was followed using 3-tert-butoxyamido-piperidine instead of tert-butyl piperazine-l-carboxylate to give 2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2- oxoethyl)(methyl)amino)piperidin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile. 1 H NMR (400 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 4.58 (m, 1H), 4.38 (m, 1H), 4.23 (m, 1H), 4.04 (m, 1H), 3.85 (m, 2H), 3.69 (m, 1H), 3.58 (s, 3H), 3.20 (m, 2H), 3.00 (m, 2H), 2.72 (m, 1H), 2.58 (q, J = 7.6 Hz, 2H), 2.00 (m, 1H), 1.86 (m, 1H), 1.51 (m, 2H), 1.27 (t, J = 7.6 Hz, 3H).

[0475] Example 15

[0476] 1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-ethylimidazo[2,l- b][l,3,4]thiadiazol-2-yl]piperidin-3-yl}-l-methylurea

[0477]

[0478] Reference Example 7 was followed using 3-tert-butoxyamido-piperidine instead of tert-butyl piperazine-l-carboxylate to give 1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2- yl)(methyl)amino)-6-ethylimidazo[2,l-b][l,3,4]thiadiazol-2-yl]piperidin-3-yl}-l- methylurea. 1H NMR (400 MHz, CDC13) δ: 8.15 (m, 2H), 7.15 (m, 2H), 4.57 (s, 2H), 4.23 (m, 1H), 3.91 (m, 0.5H), 3.77 (m, 1H), 3.66 (m, 0.5H), 3.57 (s, 3H), 3.00 (m, 2H), 2.84 (s, 3H), 2.59 (q, J = 7.6 Hz, 2H), 1.93 (m, 2H), 1.77 (m, 2H), 1.27 (t, J = 7.6 Hz, 3H).

[0479] Example 16

[0480] Preparation of 2-{[6-ethyl-2-(1-(methylsulfonyl)piperidin-4-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0481]

[0482] Step 1): 5-(Piperidin-4-yl)-1,3,4-thiadiazol-2-amine

[0483] Dissolve 4-piperidinecarboxylic acid (10 g, 77.4 mmol) in concentrated hydrochloric acid (150 mL) and water (25 mL), add thiosemicarbazide (14.1 g, 154.8 mmol), and react at 120 °C overnight. Spin off part of the solvent, and adjust the pH to about 10 with a saturated sodium hydroxide solution. After stirring for 30 minutes, filter, and recrystallize the filter cake from ethanol to obtain 2.9 g of a white solid, yield: 20%. MS (m / z): 185.1 [M+1].

[0484] Step 2): 4-(5-Amino-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylic acid benzyl ester

[0485] Dissolve 5-(piperidin-4-yl)-1,3,4-thiadiazol-2-amine (2.6 g, 14.1 mmol) in acetonitrile (30 mL) and water (10 mL), add sodium bicarbonate (1.78 g, 21.2 mmol), cool to 0 °C, and dropwise add CbzCl (2.21 mL, 15.5 mmol). React at 0 °C for 2 hours. Add water (20 mL), extract with ethyl acetate (50 mL x 3), combine the organic layers, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, spin dry, and purify by column chromatography (dichloromethane:methanol = 40:1) to obtain 800 mg of a light yellow solid, yield: 18%. MS (m / z): 319.2 [M+1].

[0486] Step 3): 4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2, 1-b] [1,3,4]thiadiazol-2-yl}piperidine- 1 -carboxylic acid benzyl ester

[0487] Reference Example 1 for the preparation of 4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2, 1-b] [1,3,4]thiadiazol-2-yl}piperazine- 1 -carboxylic acid tert-butyl ester using 4-(5-amino- 1,3,4-thiadiazol-2-yl)piperidine- 1 -carboxylic acid benzyl ester instead of 2-amino-5-bromo- 1,3,4-thiadiazole to give 4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2, 1-b] [1,3,4]thiadiazol-2-yl}piperidine- 1 -carboxylic acid benzyl ester. 1 H NMR (400 MHz, CDC13) δ: 8.14 (m, 2H), 7.35 (m, 5H), 7.16 (m, 2H), 5.14 (s, 2H), 4.28 (m, 2H), 3.61 (s, 3H), 3.16 (m, 1H), 2.97 (m, 2H), 2.64 (q, J = 7.6 Hz, 2H), 2.10 (m, 2H), 1.78 (m, 2H), 1.31 (t, J = 7.6 Hz, 3H).

[0488] Step 4): 2-{[6-ethyl-2-(piperidin-4-yl)imidazo[2, 1-b] [1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0489] Benzyl 4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2, 1-b] [1,3,4]thiadiazol-2-yl}piperidine- 1 -carboxylic acid benzyl ester (330 mg, 0.55 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0 °C, trimethylsilyl iodide (220 mg, 1.1 mmol) was added and the reaction was allowed to proceed at room temperature for three hours. The dichloromethane was evaporated and water (20 mL) was added. The impurities were extracted with petroleum ether and the aqueous layer was adjusted to pH 8 with sodium bicarbonate solution and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated to give 260 mg of a foam as a solid which was used without purification in the next step. MS (m / z): 468.1 [M+1].

[0490] Step 5): 2-{[6-ethyl-2-(l-(methylsulfonyl)piperidin-4-yl)imidazo[2, 1-b] [1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0491] Reference Example 1 was followed using 2-{[6-ethyl-2-(piperidin-4- yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole- 5-carbonitrile in place of 2-{[6-ethyl-2-(piperazin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol- 5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile to give 2-{[6-ethyl-2- (1-(methylsulfonyl)piperidin-4-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile. 1 H NMR (500 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 3.90 (m, 2H), 3.62 (s, 3H), 3.13 (m, 1H), 2.87 (m, 2H), 2.82 (s, 3H), 2.64 (q, J = 7.5 Hz, 2H), 2.24 (m, 2H), 1.99 (m, 2H), 1.31 (t, J = 7.5 Hz, 3H).

[0492] Example 17

[0493] Preparation of 2-{[6-ethyl-2-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4- yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile

[0494]

[0495] Reference Example 2 was followed using 2-{[6-ethyl-2-(piperidin-4- yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole- 5-carbonitrile in place of 2-{[6-ethyl-2-(piperazin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol- 5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile to give 2-{[6-ethyl-2- (1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[2,1-b][1,3,4]thiadiazol- 5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. 1H NMR (500 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 4.68 (m, 1H), 4.44 (m, 1H), 4.27 (m, 1H), 4.08 (m, 1H), 3.89 (m, 1H), 3.61 (s, 3H), 3.05 (m, 2H), 2.98 (m, 3H), 2.64 (q, J = 7.5 Hz, 2H), 2.23 (m, 2H), 2.10 (m, 2H), 1.92 (m, 2H), 1.30 (t, J = 7.5 Hz, 3H).

[0496] Example 18

[0497] Preparation of 4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}piperidine-1-carboxamide

[0498]

[0499] Referring to Example 7, 4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}piperidine-1-carboxamide was prepared using 2-{[6-ethyl-2-(piperidin-4-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile instead of 2-{[6-ethyl-2-(piperazin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. 1 H NMR (500 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 4.68 (m, 1H), 4.44 (m, 1H), 4.27 (m, 1H), 4.08 (m, 1H), 3.89 (m, 1H), 3.61 (s, 3H), 3.05 (m, 2H), 2.98 (m, 3H), 2.64 (q, J = 7.5 Hz, 2H), 2.23 (m, 2H), 2.10 (m, 2H), 1.92 (m, 2H), 1.30 (t, J = 7.5 Hz, 3H).

[0500] Example 19

[0501] Preparation of (R)-1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-1-methylurea

[0502]

[0503] Referring to Example 7, (S)-1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2- yl)(methyl)amino)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-1- methylurea was prepared using (S)-3-tert-butoxycarbonylamino tetrahydropyrrolidine in place of tert-butyl piperazine-1-carboxylate. 1 H NMR (500 MHz, CDC13) δ: 8.14 (m, 2H), 7.15 (m, 2H), 5.19 (m, 1H), 4.63 (s, 2H), 3.65 (m, 2H), 3.57 (s, 3H), 3.45 (m, 1H), 3.32 (s, 1H), 2.84 (s, 3H), 2.26 (q, J = 9.5 Hz, 2H), 2.25 (m, 1H), 2.11 (m, 1H), 1.28 (m, 3H). MS (m / z): 526.2 [M+1].

[0504] Example 20

[0505] Preparation of (S)-1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-1-methylurea

[0506]

[0507] Referring to Example 7, (S)-1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2- yl)(methyl)amino)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-1- methylurea was prepared using (S)-3-tert-butoxycarbonylamino tetrahydropyrrolidine in place of tert-butyl piperazine-1-carboxylate. 1 H NMR (500 MHz, CDC13) δ: 8.14 (m, 2H), 7.15 (m, 2H), 5.19 (m, 1H), 4.63 (s, 2H), 3.65 (m, 2H), 3.57 (s, 3H), 3.45 (m, 1H), 3.32 (s, 1H), 2.84 (s, 3H), 2.26 (q, J = 9.5 Hz, 2H), 2.25 (m, 1H), 2.11 (m, 1H), 1.28 (m, 3H). MS (m / z): 526.2 [M+1].

[0508] Example 21

[0509] (R)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)(methyl)amino) tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0510]

[0511] (R)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)(methyl)amino) tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile was prepared according to Example 2 using (R)-3-tert- butoxyamidotetrahydropyrrolidine instead of piperazine- 1-carboxylic acid tert-butyl ester. 1 H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.69 (m, 1H), 4.43 (m, 1H), 4.29 (m, 1H), 4.07 (m, 1H), 3.91 (m, 1H), 3.67 (m, 1H), 3.60 (m, 4H), 3.49-3.31 (m, 3H), 3.16 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 2.46 (m, 1H), 2.38 (s, 3H), 2.25 (m, 1H), 1.30 (t, J = 7.6 Hz, 3H). MS (m / z): 596.2 [M+l].

[0512] Example 22

[0513] (R)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)(methyl)amino) tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0514]

[0515] (R)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)(methyl)amino) tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile was prepared according to Example 2 using (S)-3-tert- butoxyamidotetrahydropyrrolidine instead of piperazine- 1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.70 (m, 1H), 4.44 (m, 1H), 4.29 (m, 1H), 4.08 (m, 1H), 3.91 (m, 1H), 3.67 (m, 1H), 3.60 (m, 4H), 3.49-3.32 (m, 3H), 3.17 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 2.38 (s, 3H), 2.28 (m, 2H), 1.30 (t, J = 7.6 Hz, 3H). MS (m / z): 596.2 [M+l].

[0516] Example 23

[0517] Preparation of (R)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2- oxoehtyl)(methyl)amino)piperidin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0518]

[0519] (R)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2- oxoehtyl)(methyl)amino)piperidin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared according to the procedure of Reference Example 2, using (R)-3-tert-butoxycarbonylamino piperidine instead of tert-butyl piperazine-l-carboxylate. 1 H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.70 (m, 1H), 4.44 (m, 1H), 4.29 (m, 1H), 4.08 (m, 1H), 3.91 (m, 1H), 3.67 (m, 1H), 3.60 (m, 4H), 3.49-3.32 (m, 3H), 3.17 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 2.38 (s, 3H), 2.28 (m, 2H), 1.30 (t, J = 7.6 Hz, 3H). MS (m / z): 596.2 [M+l].

[0520] Example 24

[0521] Preparation of (S)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2- oxoehtyl)(methyl)amino)piperidin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0522]

[0523] Referring to Example 2, (S)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2- oxoehtyl)(methyl)amino)piperidin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared using (S)-3-tert-butoxycarbonylaminopiperidine instead of tert-butyl piperazine-l-carboxylate. 1 H NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 4.61 (m, 1H), 4.40 (m, 1H), 4.26 (m, 1H), 4.08 (m, 1H), 3.87 (m, 2H), 3.69 (m, 1H), 3.60 (s, 3H), 3.22 (m, 2H), 3.03 (m, 2H), 2.74 (m, 1H), 2.61 (q, J = 7.6 Hz, 2H), 2.40 (m, 3H), 2.03 (m, 2H), 1.89 (m, 1H), 1.54 (m, 2H), 1.30 (t, J = 7.6 Hz, 3H). MS (m / z): 610.2 [M+l].

[0524] Example 25

[0525] Preparation of 3-tert-butyl-l-{l-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,l-b][l,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-l-methylurea

[0526]

[0527] Step 1): Preparation of 2-{[6-ethyl-2-(3-(methylamino)tetrahydropyrrol-l-yl)imidazo[2,l- b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0528] Reference Example 1 was followed using 3-tert-butoxycarbonylpyrrolidine in place of tert-butyl piperazine-1-carboxylate to give 2-{[6-ethyl-2-(3-(methylamino)pyrrolidin-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. MS (m / z): 483.2 [M+1].

[0529] Step 2) Preparation of 3-tert-butyl-1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]piperidin-3-yl}-1-methylurea

[0530] To 2-{[6-ethyl-2-(3-(methylamino)pyrrolidin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile (48 mg, 0.10 mmol) in tetrahydrofuran was added tert-butyl isocyanate (15 mg, 0.15 mmol) and the reaction was stirred at 50 °C for 3 h. The solvent was evaporated and the crude was purified by preparative TLC to give 41 mg of white solid, yield: 71%. 1 H NMR (400 MHz, CDC13) δ: 8.15 (m, 2H), 7.17 (m, 2H), 4.31 (m, 1H), 3.76 (m, 1H), 3.67-3.60 (m, 5H), 3.47 (m, 1H), 3.28 (m, 1H), 2.78 (s, 3H), 2.63 (m, 2H), 2.24 (m, 1H), 2.10 (m, 1H), 1.37 (s, 9H), 1.27 (m, 3H). MS (m / z): 582.2 [M+1].

[0531] Example 26

[0532] Preparation of 3-tert-butyl-1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]piperidin-3-yl}-1-methylurea

[0533]

[0534] Reference Example 25 was followed using 3-tert-butoxycarbonylpiperidine in place of 3-tert-butoxycarbonylpyrrolidine to give 3-tert-butyl-1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]piperidin-3-yl}-1-methylurea. 1HNMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.17 (m, 2H), 4.26 (s, IH), 3.88-3.65 (m, 3H), 3.60 (s, 3H), 2.97 (m, 2H), 2.78 (s, 3H), 2.62 (m, 2H), 1.91 (m, 2H), 1.78 (m, 2H), 1.37 (s, 9H), 1.27 (m, 3H).

[0535] Example 27

[0536] Preparation of 1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-3-cyclopropyl-1- methylurea

[0537]

[0538] To a round bottom flask was added triphosgene (24.5 mg, 0.083 mmol), dichloromethane (2 mL), and cooled to 0 °C under nitrogen. To another round bottom flask was added cyclopropylamine (17 μL, 0.25 mmol), triethylamine (86 μL, 0.62 mmol) and dichloromethane (1 mL), and this reaction was added dropwise to the above flask. After half an hour at 0 °C, 2-{[6-ethyl-2-(3-(methylamino)tetrahydropyrrol-l-yl)imidazo[2,l- b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile (30 mg, 0.062 mmol) was added and slowly warmed to room temperature overnight. It was dried and purified by thick prep plate (dichloromethane:methanol = 20:1) to give 26 mg of light yellow solid, yield: 74%. 1 H NMR (500 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 5.23 (m, IH), 4.70 (s, IH), 3.72-3.60 (m, 5H), 3.48 (m, IH), 3.32 (m, IH), 2.78 (s, 3H), 2.68-2.58 (m, 3H), 2.26 (m, IH), 2.14 (m, IH), 1.30 (t, J = 7.2 Hz, 3H), 0.76 (m, 2H), 0.50 (m, 2H). MS (m / z): 566.4 [M+l].

[0539] Example 28

[0540] Preparation of N-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-N-methylcyclopropane sulfonamide

[0541]

[0542] Preparation of N-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-N-methylcyclopropane sulfonamide 1 H NMR (500 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.77 (m, 1H), 3.72-3.61 (m, 5H), 3.49 (m, 2H), 2.92 (s, 3H), 2.63 (q, J = 7.6 Hz, 2H), 2.33 (m, 3H), 1.31 (t, J = 7.6 Hz, 3H), 1.23 (m, 2H), 1.06 (m, 2H). MS (m / z): 587.3 [M+1].

[0543] Example 29

[0544] Preparation of 1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-1,3-dimethylurea

[0545]

[0546] Referring to Example 27, 1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-1,3-dimethylurea was prepared by replacing cyclopropylamine with methylamine tetrahydrofuran solution. 1H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 5.25 (m, 1H), 4.45 (m, 1H), 3.70-3.60 (m, 5H), 3.48 (m, 1H), 3.32 (m, 1H), 2.85 (d, J = 4.4 Hz, 3H), 2.82 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 2.25 (m, 1H), 2.13 (m, 1H), 1.30 (t, J = 7.6 Hz, 3H). MS (m / z): 540.3 [M + 1].

[0547] Example 30

[0548] Preparation of N-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-3-hydroxy-N- methylazetidine-1-carboxamide

[0549]

[0550] To a round bottom flask was added triphosgene (13.4 mg, 0.045 mmol), dichloromethane (2 mL), and cooled to 0 °C under nitrogen. To another round bottom flask was added 2-{[6-ethyl-2-(3-(methylamino)tetrahydropyrrol-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile (27 mg, 0.057 mmol), triethylamine (39 μL, 0.28 mmol), and dichloromethane (1 mL), and this solution was added dropwise to the above flask. After half an hour at 0 °C, azetidin-3-ol hydrochloride (31 mg, 0.28 mmol) and triethylamine (39 μL, 0.28 mmol) were added, and the reaction was allowed to slowly warm to room temperature overnight. It was then concentrated and purified by thick plate (dichloromethane:methanol = 16:1) to give 21 mg of white solid in 65% yield. 1 H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 5.25 (m, 1H), 4.45 (m, 1H), 3.70-3.60 (m, 5H), 3.48 (m, 1H), 3.32 (m, 1H), 2.85 (d, J = 4.4 Hz, 3H), 2.82 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 2.25 (m, 1H), 2.13 (m, 1H), 1.30 (t, J = 7.6 Hz, 3H). MS (m / z): 540.3 [M + 1].

[0551] Example 31

[0552] 1-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-1,3,3- trimethylurea

[0553]

[0554] Dissolve 2-{[6-ethyl-2-(3-(methylamino)tetrahydropyrrol-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile (25 mg, 0.052 mmol) in THF (2 mL) under nitrogen protection, stir and cool to 0 °C. Add triethylamine (22 μL, 0.16 mmol), then drop dimethylcarbamoyl chloride (7 mg, 0.067 mmol), after 15 min at 0 °C, slowly raise to room temperature and react overnight. Dry and purify by thick preparative plate (dichloromethane:methanol = 25:1) to obtain 24 mg of white solid, yield: 83%. 1 H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.43 (m, 1H), 3.81 (m, 1H), 3.65 (m, 1H), 3.60 (m, 3H), 3.49 (m, 1H), 3.37 (m, 1H), 2.87 (s, 6H), 2.80 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 2.32 (m, 1H), 2.18 (m, 1H), 1.29 (m, 3H). MS (m / z): 554.36 [M+1].

[0555] Example 32

[0556] Preparation of N-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)- 6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-N- methylmorpholine-4-carboxamide

[0557]

[0558] N-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-N- methylmorpholine-4-carboxamide was prepared according to Example 31 by replacing dimethylcarbamoyl chloride with 4-morpholinecarboxylic acid chloride. 1H NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 4.52 (m, 1H), 3.18 (m, 1H), 3.72-3.64 (m, 5H), 3.60 (s, 3H), 3.50 (m, 1H), 3.38 (m, 1H), 3.30 (m, 4H), 2.85 (s, 3H), 2.63 (q, J = 7.6 Hz 2H), 2.33 (m, 1H), 2.19 (m, 1H), 1.29 (s, 3H). MS (m / z): 596.38 [M+1].

[0559] Example 33

[0560] Preparation of 2-{[6-ethyl-2-(3-((2-(3-fluoroazetidin-1-yl)-2-oxoethyl)(methyl)amino) tetrahydropyrrol-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0561]

[0562] Reference Example 11 was followed using 2-chloro-1-(3-fluoroazetidin-1-yl)ethanone in place of 2-chloro-1-(3-hydroxyazetidin-1-yl)ethanone to give 2-{[6-ethyl-2-(3-((2-(3- fluoroazetidin-1-yl)-2-oxoethyl)(methyl)amino)tetrahydropyrrol-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. 1 H NMR (500 MHz, CDC13) δ: 8.18 (m, 2H), 7.18 (m, 2H), 5.40-5.26 (m, 1H), 5.51 (m, 1H), 4.36 (m, 2H), 4.17 (m, 1H), 3.68-3.61 (m, 5H), 3.50-3.31 (m, 3H), 3.20 (s, 2H), 2.63 (q, J = 9.5 Hz, 2H), 2.38 (s, 3H), 2.27 (m, 1H), 2.04 (m, 1H). MS (m / z): 598.3 [M+1].

[0563] Example 34

[0564] Preparation of 2-{[6-ethyl-2-(3-(methyl(2-morpholino-2-oxoethyl)amino)tetrahydropyrrol-1- yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile

[0565]

[0566] 2-{[6-ethyl-2-(3-(methyl(2-morpholino-2-oxoethyl)amino)tetrahydropyran-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared according to Reference Example 11 using 2-chloro-1 -morpholinoethanone instead of 2-chloro-1 -(3-hydroxyazetidin-1 -yl)ethanone. 1 H NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 3.73-3.67 (m, 6H), 3.65-3.60 (m, 8H), 3.50-3.43 (m, 2H), 3.32-3.29 (m, 3H), 2.62 (q, J = 7.6 Hz, 2H), 2.40 (s, 3H), 2.26 (m, 1H), 2.05 (m, 1H), 1.30 (m, 3H). MS (m / z): 610.4 [M+1].

[0567] Example 35

[0568] 1-{2-[(1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyran-3-yl)(methyl)amino]acetyl}azetidine- 3-carboxylic acid

[0569]

[0570] To a solution of 2-{[6-ethyl-2-(3-(methylamino)tetrahydropyrrol-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile (110 mg, 0.228 mmol) in acetonitrile (5 mL) was added triethylamine (95 μL, 0.685 mmol) under nitrogen atmosphere and stirred while cooling to 0 °C. 1-(2-chloroacetyl)azetidine-3-carboxylate (65 mg, 0.342 mmol) was added and the reaction was allowed to proceed at 0 °C for 10 min and then at 80 °C overnight. Additional 1-(2-chloroacetyl)azetidine-3-carboxylate (33 mg, 0.171 mmol) was added and the reaction was allowed to proceed for 5 h. The reaction was complete and was concentrated in vacuo. The residue was purified by thick prep plate (dichloromethane:methanol = 15:1) to give a white solid 84 mg. The white solid was dissolved in THF (2 mL) and stirred while cooling to 0 °C. 0.5 N sodium hydroxide solution (0.5 mL) was added dropwise slowly. The reaction was allowed to proceed for 30 min. THF was removed in vacuo. Water (5 mL) was added and the pH was adjusted to about 5. A white solid was precipitated. The solid was collected by filtration. The filter cake was purified by thick prep plate (dichloromethane:methanol = 12:1) to give a white solid 31 mg. Yield: 22 %. 1 H NMR (400 MHz, CD3OD) δ: 8.12 (m, 2H), 7.24 (m, 2H), 4.44 (m, 2H), 4.14 (m, 2H), 3.70 (m, 1H), 3.62 (m, 1H), 3.58 (s, 3H), 3.49-3.37 (m, 4H), 3.23 (s, 2H), 2.58 (q, J = 7.6 Hz, 2H), 2.35 (s, 3H), 2.27 (m, 1H), 2.06 (m, 1H), 1.29 (m, 3H). MS (m / z): 624.3 [M+1].

[0571] Example 36

[0572] Preparation of (R)-N-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-3-hydroxy-N- methylazetidine-1-carboxamide

[0573]

[0574] Referring to Example 30, (S)-N-{l-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2- yl)(methyl)amino)-6-ethylimidazo[2,l-b][l,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-3- hydroxy-N-methylazetidine-l-carboxamide was prepared using (S)-3-tert-butoxyamino tetrahydropyrrolidine instead of 3-tert-butoxyamino tetrahydropyrrolidine. 1 H NMR (400 MHz, CDC13) δ: 1 H NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 4.88 (m, IH), 4.63 (m, IH), 4.22 (m, 2H), 3.88 (m, 2H), 3.71-3.60 (m, 5H), 3.48 (m, IH), 3.36 (m, IH), 2.80 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 2.40 (m, IH), 2.26 (m, IH), 2.17 (m, IH), 1.30 (t, J = 7.6 Hz, 3H). MS (m / z): 582.2 [M+l].

[0575] Example 37

[0576] Preparation of (S)-N-{l-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,l-b][l,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-3-hydroxy-N- methylazetidine-l-carboxamide

[0577]

[0578] Referring to Example 30, (S)-N-{l-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2- yl)(methyl)amino)-6-ethylimidazo[2,l-b][l,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-3- hydroxy-N-methylazetidine-l-carboxamide was prepared using (S)-3-tert-butoxyamino tetrahydropyrrolidine instead of 3-tert-butoxyamino tetrahydropyrrolidine. 1 H NMR (400 MHz, CDC13) δ: 1H NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 4.87 (m, 1H), 4.63 (m, 1H), 4.23 (m, 2H), 3.88 (m, 2H), 3.71-3.60 (m, 5H), 3.48 (m, 1H), 3.36 (m, 1H), 2.80 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 2.41 (m, 1H), 2.26 (m, 1H), 2.18 (m, 1H), 1.30 (t, J = 7.6 Hz, 3H). MS (m / z): 582.2 [M+l].

[0579] Example 38

[0580] (S)-2-{[6-ethyl-2-(3-((2-(3-fluoroazetidin-l-yl)-2-oxoethyl)(methyl)amino) tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0581]

[0582] (S)-2-{[6-ethyl-2-(3-((2-(3-fluoroazetidin-l-yl)-2-oxoethyl)(methyl)amino) tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile was prepared according to the procedure described in Reference Example 33, using (S)-3-tert-butoxyamidotetrahydropyrrolidine instead of 3-tert- butoxyamidotetrahydropyrrolidine. 1 H NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 4.87 (m, 1H), 4.63 (m, 1H), 4.23 (m, 2H), 3.88 (m, 2H), 3.71-3.60 (m, 5H), 3.48 (m, 1H), 3.36 (m, 1H), 2.80 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 2.41 (m, 1H), 2.26 (m, 1H), 2.18 (m, 1H), 1.30 (t, J = 7.6 Hz, 3H). MS (m / z): 582.2 [M+l].

[0583] Example 39

[0584] (R)-2-{[6-ethyl-2-(3-((2-(3-fluoroazetidin-l-yl)-2-oxoethyl)(methyl)amino) tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0585]

[0586] (R)-2-{[6-ethyl-2-(3-((2-(3-fluoroazetidin-l-yl)-2-oxoethyl)(methyl)amino) tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile was prepared according to the procedure described in Reference Example 33, using (R)-3-tert-butoxyacylamino tetrahydropyrrolidine instead of 3-tert-butoxyacylamino tetrahydropyrrolidine. 1 H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 5.40-5.25 (m, IH), 4.51 (m, IH), 4.34 (m, 2H), 4.16 (m, IH), 3.70-3.59 (m, 5H), 3.52-3.31 (m, 3H), 3.19 (s, 2H), 2.61 (q, J = 7.2 Hz, 2H), 2.38 (s, 3H), 2.27 (m, IH), 2.03 (m, IH), 1.30 (m, 3H). MS (m / z): 598.2 [M+l].

[0587] Example 40

[0588] (R)-2-{[6-ethyl-2-(3-((2-(3-fluoroazetidin-l-yl)-2-oxoethyl)(methyl)amino) tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0589]

[0590] (R)-2-{[6-ethyl-2-(3-((2-(3-fluoroazetidin-l-yl)-2-oxoethyl)(methyl)amino) tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile was prepared according to the procedure described in Reference Example 34, using (R)-3-tert-butoxyacylamino tetrahydropyrrolidine instead of 3-tert-butoxyacylamino tetrahydropyrrolidine. 1HNMR (400 MHz, CDC13) δ: 8.15 (m, 2H), 7.16 (m, 2H), 3.66 (m, 5H), 3.60-3.57 (m, 8H), 3.48-3.41 (m, 2H), 3.36-3.29 (m, 3H), 2.60 (q, J = 7.6 Hz, 2H), 2.37 (s, 3H), 2.25 (m, IH), 2.03 (m, IH), 1.28 (m, 3H). MS (m / z): 610.3 [M+l].

[0591] Example 41

[0592] Preparation of (S)-2-{[6-ethyl-2-(3-(methyl(2-morpholino-2-oxoethyl)amino)tetrahydropyrrol-1- yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile

[0593]

[0594] Referring to Example 34, (S)-2-{[6-ethyl-2-(3-(methyl(2-morpholino-2-oxoethyl)amino)tetrahydropyrrol-1- yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile was prepared using (S)-3-tert-butoxyamidotetrahydropyrrolidine in place of 3-tert-butoxyamidotetrahydropyrrolidine. 1 HNMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 3.69 (m, 5H), 3.65-3.60 (m, 8H), 3.50-3.46 (m, 2H), 3.38-3.31 (m, 3H), 2.62 (q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 2.26 (m, IH), 2.05 (m, IH), 1.31 (m, 3H). MS (m / z): 610.4 [M+l].

[0595] Example 42

[0596] Preparation of (R)-1-{2-[(1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl)(methyl)amino]acetyl}azetidine-3- carboxylic acid methyl ester

[0597]

[0598] (R)-1-{2-[(1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl)(methyl)amino]acetyl}azetidine- 3-carboxylic acid methyl ester was prepared according to Reference Example 21 using 1-(2- chloroacetyl)azetidine-3-carboxylic acid methyl ester instead of 2-chloro-1-(3- hydroxyazetidin-1-yl)ethanone. MS (m / z): 638.3 [M+1].

[0599] Example 43

[0600] Preparation of (S)-1-{2-[(1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl)(methyl)amino]acetyl}azetidine- 3-carboxylic acid methyl ester

[0601]

[0602] (S)-1-{2-[(1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl)(methyl)amino]acetyl}azetidine- 3-carboxylic acid methyl ester was prepared according to Reference Example 22 using 1-(2- chloroacetyl)azetidine-3-carboxylic acid methyl ester instead of 2-chloro-1-(3- hydroxyazetidin-1-yl)ethanone. MS (m / z): 638.3 [M+1].

[0603] Example 44

[0604] Preparation of (R)-1-{2-[(1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl)(methyl)amino]acetyl}azetidine- 3-carboxylic acid

[0605]

[0606] (R)-1-{2-[(1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl)(methyl)amino]acetyl}azetidine- 3-carboxylic acid was prepared according to Reference Example 35 using (R)-3-tert-butoxyacylamino tetrahydropyrrolidine instead of 3-tert-butoxyacylamino tetrahydropyrrolidine.1 H NMR (500 MHz, CD3OD) δ: 8.13 (m, 2H), 7.24 (m, 2H), 4.52 (t, 1H), 4.38 (m, 1H), 4.18 (m, 1H), 4.09 (m, 1H), 3.71 (m, 1H), 3.63 (m, 1H), 3.59 (s, 3H), 3.51-3.37 (m, 4H), 3.24 (s, 2H), 2.60 (q, J = 7.5 Hz, 2H), 2.36 (s, 3H), 2.27 (m, 1H), 2.07 (m, 1H), 1.28 (m, 3H). MS (m / z): 624.3 [M+1].

[0607] Example 45

[0608] (S)-1-{2-[(1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl)(methyl)amino]acetyl}azetidine-3- carboxylic acid

[0609]

[0610] (S)-1-{2-[(1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl)(methyl)amino]acetyl}azetidine-3- carboxylic acid was prepared according to the procedure described in Reference Example 35, using (S)-3-tert- butoxyamidotetrahydropyrrolidine instead of 3-tert-butoxyamidotetrahydropyrrolidine. 1 H NMR (500 MHz, CD3OD) δ: 8.13 (m, 2H), 7.24 (m, 2H), 4.52 (t, 1H), 4.38 (m, 1H), 4.18 (m, 1H), 4.09 (m, 1H), 3.71 (m, 1H), 3.63 (m, 1H), 3.59 (s, 3H), 3.51-3.37 (m, 4H), 3.24 (s, 2H), 2.60 (q, J = 7.5 Hz, 2H), 2.36 (s, 3H), 2.27 (m, 1H), 2.07 (m, 1H), 1.28 (m, 3H). MS (m / z): 624.3 [M+1].

[0611] Example 46

[0612] (R)-2-{[2-(3-((2-(3-cyanooxetan-l-yl)-2-oxoethyl)(methyl)amino)tetrahydropyrrol-l- yl)-6-ethylimidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole- 5-carbonitrile

[0613]

[0614] Referring to Example 21, (R)-2-{[2-(3-((2-(3-cyanooxetan-l-yl)-2-oxoethyl)(methyl)amino)tetrahydropyrrol-l-yl)-6-ethylimidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4- (4-fluorophenyl)thiazole-5-carbonitrile was prepared using 2-chloro-l-(3-cyanooxetan-l- yl)ethanone instead of 2-chloro-l-(3-hydroxyoxetan-l-yl)ethanone. 1 H NMR (500 MHz, CDC13) δ: 8.15 (m, 2H), 7.16 (m, 2H), 4.55 (t, IH), 4.49 (m, IH), 4.33 (t, IH), 4.26 (m, IH), 3.66 (m, IH), 3.59 (m, 4H), 3.52-3.43 (m, 2H), 3.39-3.29 (m, 2H), 3.18 (q, J = 6.0 Hz, 2H), 2.60 (q, J = 7.5 Hz, 2H), 2.35 (s, 3H), 2.24 (m, IH), 2.00 (m, IH), 1.28 (t, 3H). MS (m / z): 605.3 [M+l].

[0615] Example 47

[0616] (R)-2-{[2-(3-((2-(3-cyanooxetan-l-yl)-2-oxoethyl)(methyl)amino)tetrahydropyrrol-l- yl)-6-ethylimidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole- 5-carbonitrile

[0617]

[0618] Prepared according to the procedure described in Reference Example 22 using 2-chloro-1-(3- cyanooxazolidin-1-yl)ethanone instead of 2-chloro-1-(3-hydroxyazetidin-1-yl)ethanone to give (S)-2-{[2-(3-((2-(3-cyanooxazolidin-1-yl)-2-oxoethyl)(methyl)amino)tetrahydropyran-1-yl)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile. 1 H NMR (500 MHz, CDC13) δ: 8.15 (m, 2H), 7.16 (m, 2H), 4.55 (t, 1H), 4.50 (m, 1H), 4.33 (t, 1H), 4.26 (m, 1H), 3.66 (m, 1H), 3.59 (m, 4H), 3.52-3.43 (m, 2H), 3.32-3.29 (m, 2H), 3.18 (q, J = 6.0 Hz, 2H), 2.60 (q, J = 7.5 Hz, 2H), 2.35 (s, 3H), 2.24 (m, 1H), 2.00 (m, 1H), 1.28 (t, 3H). MS (m / z): 605.4 [M+1].

[0619] Example 48

[0620] Preparation of 2-{[1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyran-3-yl](methyl)amino}ethyl acetate

[0621]

[0622] Dissolve 2-{[6-ethyl-2-(3-(methylamino)tetrahydropyran-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5- yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile (1.03 g, 2.14 mmol) in acetonitrile (25 mL), add potassium carbonate (1.18 g, 8.56 mmol), stir at room temperature for 15 minutes, then add ethyl bromoacetate (536 mg, 3.21 mmol), react at room temperature for 3 hours. Filter, wash, spin dry the filtrate, dissolve in ethyl acetate (60 mL), wash successively with water and saturated brine, dry the organic layer over anhydrous sodium sulfate, filter, spin dry, purify by column chromatography (petroleum ether: ethyl acetate = 1:1) to give a yellow thick substance 760 mg, yield: 62%. 1H-NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.17 (m, 2H), 4.21 (q, J = 7.2 Hz, 2H), 3.72-3.60 (m, 2H), 3.60 (s, 3H), 3.55-3.50 (m, 1H), 3.49-3.41 (m, 1H), 3.37 (m, 2H), 3.33-3.30 (m, 1H), 2.62 (q, J = 7.6 Hz, 2H), 2.48 (s, 3H), 2.30-2.22 (m, 1H), 2.09-1.98 (m, 1H), 1.32-1.28 (m, 3H). MS (m / z): 569.3 [M+1].

[0623] Example 49

[0624] Preparation of 2-{[l-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,l-b][l,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl](methyl)amino}acetic acid

[0625]

[0626] Ethyl 2-{[l-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,l-b][l,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl](methyl)amino}acetate (660 mg, 1.16 mmol) was dissolved in tetrahydrofuran (6 mL) and methanol (6 mL), water (3 mL) and lithium hydroxide monohydrate (243 mg, 5.80 mmol) were added and the reaction was allowed to proceed at room temperature for 16 hours. The solvents were evaporated and the residue was dissolved in water (25 mL) and stirred until the pH was adjusted to 3-4 with 1 N hydrochloric acid. A white solid was precipitated and filtered, and the filter cake was washed with water and dried under vacuum to give 610 mg of a white solid in 97% yield. 1 H-NMR (400 MHz, DMSO) δ: 8.08 (m, 2H), 7.42 (m, 2H), 3.67-3.58 (m, 2H), 3.54 (s, 3H), 3.46-3.38 (m, 2H), 3.35 (s, 2H), 3.30-3.25 (m, 1H), 2.54-2.48 (m, 2H), 2.39 (s, 3H), 2.22-2.14 (m, 1H), 2.00-1.91 (m, 1H), 1.19 (t, J = 7.6 Hz, 3H). MS (m / z): 541.3 [M+1].

[0627] Example 50

[0628] Preparation of methyl 2-{2-[(1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl)(methyl)amino]acetamido}acetate

[0629]

[0630] Glycine methyl ester hydrochloride (70 mg, 0.56 mmol) was suspended in dichloromethane (20 mL), triethylamine (112 mg, 1.12 mmol) was added and stirred at room temperature for 30 minutes. Then 2-{[1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl](methyl)amino}acetic acid (200 mg, 0.37 mmol) and HATU (169 mg, 0.44 mmol) were added and reacted at room temperature for 16 hours. The reaction was poured into water and extracted with dichloromethane (30 mL x 3), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give 180 mg of a white solid, yield: 80%. 1 H-NMR (400 MHz, CDC13) δ: 8.18 (m, 2H), 7.56 (s, 1H), 7.20 (m, 2H), 4.11 (s, 2H), 3.79 (s, 3H), 3.72 (m, 1H), 3.65 (m, 1H), 3.63 (s, 3H), 3.55-3.46 (m, 1H), 3.45-3.35 (m, 2H), 3.20 (m, 2H), 2.62 (m, 2H), 2.45 (s, 3H), 2.34-2.24 (m, 1H), 2.09 (m, 1H), 1.32 (m, 3H). MS (m / z): 612.3 [M+1].

[0631] Example 51

[0632] Preparation of 2-{2-[(1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl)(methyl)amino]acetamido}acetic acid

[0633]

[0634] Methyl 2-{2-[(1-(5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl)(methyl)amino]acetamido}acetate (80 mg, 0.13 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), water (1 mL) and lithium hydroxide monohydrate (30 mg, 0.65 mmol) were added and the reaction was stirred at room temperature for 1 hour. The solvents were evaporated and the residue was dissolved in water (10 mL) and the pH was adjusted to 3-4 with 1 N hydrochloric acid. The solid was filtered off, washed with water and dried to give 60 mg of a grey solid in 77% yield. 1 H-NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.60 (s, 1H), 7.18 (m, 2H), 4.11 (s, 2H), 3.69 (m, 2H), 3.60 (s, 3H), 3.54-3.48 (m, 1H), 3.43 (m, 2H), 3.27-3.14 (m, 2H), 2.62 (m, 2H), 2.43 (s, 3H), 2.24 (m, 1H), 2.15 (m, 1H), 1.28 (m, 3H). MS (m / z): 598.3 [M+1].

[0635] Example 52

[0636] Preparation of 2-{[6-ethyl-2-(6-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,6- diazaspiro[3.4]octan-2-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0637]

[0638] Reference Example 2 was followed using tert-butyl 2,6-diazaspiro[3.4]octane-6- carboxylate hemihydrochloride salt instead of tert-butyl piperazine-1-carboxylate to give 2-{[6-ethyl-2-(6-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,6-diazaspiro[3.4]octan-2- yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile. 1H-NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.17 (m, 2H), 4.69 (m, 1H), 4.40-4.36 (m, 1H), 4.30-4.26 (m, 1H), 4.08-4.01 (m, 5H), 3.91-3.88 (m, 1H), 3.59 (s, 3H), 3.18 (m, 2H), 2.95 (m, 2H), 2.75 (t, J = 7.2 Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 2.17 (t, J = 7.2 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H). MS (m / z): 608.2 [M+l].

[0639] Example 53

[0640] Preparation of 2-{[6-ethyl-2-(6-(2-(3-cyanooxetan-l-yl)-2-oxoethyl)- 2,6-diazaspiro[3.4]oct-2-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile

[0641]

[0642] Reference Example 52 was followed using 2-chloro-l-(3-cyanooxetan-l-yl)ethanone in place of 2-chloro-l-(3-hydroxyoxetan-l-yl)ethanone to give 2-{[6-ethyl-2-(6-(2-(3-cyanooxetan-l-yl)-2-oxoethyl)-2,6-diazaspiro[3.4]oct-2-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. 1 H-NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 4.54-4.44 (m, 2H), 4.38-4.33 (m, 1H), 4.29-4.25 (m, 1H), 4.06 (m, 2H), 4.05 (m, 2H), 3.59 (s, 3H), 3.54-3.49 (m, 1H), 3.21 (s, 2H), 2.93 (s, 2H), 2.73 (t, J = 7.2 Hz, 2H), 2.62 (q, J = 7.6 Hz, 2H), 2.18 (t, J = 7.2 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H). MS (m / z): 617.2 [M+l].

[0643] Example 54

[0644] 2-{[6-ethyl-2-(2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,6-diazaspiro[3.4]octan-6- yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile

[0645]

[0646] 2-{[6-ethyl-2-(2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,6-diazaspiro[3.4]octan-6- yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile was prepared according to Example 2, using tert-butyl 2,6-diazaspiro[3.4]octane- 2-carboxylate instead of tert-butyl piperazine-1-carboxylate. 1 H-NMR (400 MHz, CDC13) δ: 8.18 (m, 2H), 7.18 (m, 2H), 4.69 (m, 1H), 4.39 (m, 1H), 4.29-4.25 (m, 1H), 4.07-4.03 (m, 1H), 3.91-3.86 (m, 1H), 3.62 (m, 2H), 3.60 (s, 3H), 3.51-3.48 (m, 2H), 3.47-3.42 (m, 4H), 3.20 (m, 2H), 2.62 (q, J = 7.6 Hz, 2H), 2.29 (m, 2H), 1.30 (m, 3H). MS (m / z): 608.2 [M + 1].

[0647] Example 55

[0648] 2-{[6-ethyl-2-(2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,6-diazaspiro[3.4]octan-6- yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile

[0649]

[0650] 2-{[6-ethyl-2-(2-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,6-diazaspiro[3.4]octan-6- yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile was prepared according to Example 54, using 2-chloro-1-(3-cyanazetidin-1- yl)ethanone instead of 2-chloro-1-(3-hydroxyazetidin-1-yl)ethanone.1 H-NMR (400 MHz, CDC13) δ: 8.18 (m, 2H), 7.18 (m, 2H), 4.57-4.52 (m, 1H), 4.50-4.46 (m, 1H), 4.36-4.31 (m, 1H), 4.27-4.22 (m, 1H), 3.60 (m, 5H), 3.55-3.51 (m, 1H), 3.50-3.47 (m, 2H), 3.37 (m, 4H), 3.18 (s, 2H), 2.62 (q, J = 7.6 Hz, 2H), 2.27 (m, 2H), 1.30 (m, 3H). MS (m / z): 617.2 [M+1].

[0651] Example 56

[0652] 2-{[6-ethyl-2-(5-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0653]

[0654] 2-{[6-ethyl-2-(5-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile was prepared according to the procedure described in Reference Example 2, using hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester. 1 H-NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 4.65 (m, 1H), 4.39-4.34 (m, 1H), 4.28-4.24 (m, 1H), 4.04-3.99 (m, 1H), 3.90-3.85 (m, 1H), 3.70-3.66 (m, 2H), 3.60 (s, 3H), 3.41-3.33 (m, 2H), 3.19-3.11 (m, 2H), 3.07-3.00 (m, 2H), 2.79-2.72 (m, 2H), 2.70-2.65 (m, 2H), 2.64-2.59 (m, 2H), 1.29 (m, 3H). MS (m / z): 608.3 [M+1].

[0655] Example 57

[0656] 2-{[6-ethyl-2-(5-(2-(3-cyanooxetan-3-yl)-2-oxoethyl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0657]

[0658] Reference Example 56 was followed using 2-chloro-l-(3-cyanooxetan-l-yl)ethanone in place of 2-chloro-l-(3-hydroxyoxetan-l-yl)ethanone to give 2-{[6-ethyl-2-(5-(2-(3- cyanooxetan-3-yl)-2-oxoethyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)imidazo[2,l- b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. 1 H-NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.52-4.42 (m, 2H), 4.37-4.32 (m, IH), 4.28-4.24 (m, IH), 3.69 (m, 2H), 3.60 (s, 3H), 3.52-3.46 (m, IH), 3.36 (m, 2H), 3.19 (s, 2H), 3.06 (m, 2H), 2.84-2.74 (m, 2H), 2.66 (m, 2H), 2.64 (m, 2H), 1.28 (m, 3H). MS (m / z): 617.3 [M+l].

[0659] Example 58

[0660] 2-{[6-ethyl-2-((lS,4S)-5-(2-(3-hydroxyoxetan-l-yl)-2-oxoethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4- (4-fluorophenyl)thiazole-5-carbonitrile

[0661]

[0662] Referring to Example 2, tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate is used instead of tert-butyl piperazine-1-carboxylate to prepare 2-{[6- ethyl-2-((1S,4S)-5-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,5-diazabicyclo[2.2.1]heptan- 2-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole- 5-carbonitrile. 1 H-NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.70 (m, 1H), 4.45-4.35 (m, 1H), 4.33-4.25 (m, 2H), 4.04 (m, 1H), 3.91-3.87 (m, 1H), 3.76 (m, 1H), 3.61 (s, 3H), 3.60-3.53 (m, 1H), 3.46-3.39 (m, 1H), 3.29-3.22 (m, 2H), 3.16-3.05 (m, 1H), 2.85-2.77 (m, 1H), 2.64 (q, J = 7.2 Hz, 2H), 2.11-2.04 (m, 1H), 1.96-1.91 (m, 1H), 1.29 (m, 3H). MS (m / z): 594.3 [M+1].

[0663] Example 59

[0664] Preparation of 2-{[6-ethyl-2-((1S,4S)-5-(2-(3-cyanooazetidin-1-yl)-2-oxoethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4- (4-fluorophenyl)thiazole-5-carbonitrile

[0665]

[0666] Referring to Example 58, 2-chloro-1-(3-cyanooazetidin-1-yl)ethanone is used instead of 2-chloro-1-(3-hydroxyazetidin-1-yl)ethanone to prepare 2-{[6-ethyl-2-((1S,4S)-5-(2- (3-cyanooazetidin-1-yl)-2-oxoethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. 1H-NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.59-4.46 (m, 2H), 4.38-4.31 (m, 2H), 4.29-4.24 (m, 1H), 3.71 (m, 1H), 3.61 (s, 3H), 3.56-3.52 (m, 1H), 3.51-3.49 (m, 1H), 3.47-3.42 (m, 1H), 3.30 (m, 2H), 3.11-3.01 (m, 1H), 2.89-2.79 (m, 1H), 2.69-2.57 (m, 2H), 2.07-2.02 (m, 1H), 1.99-1.93 (m, 1H), 1.28 (m, 3H). MS (m / z): 603.3 [M+1].

[0667] Example 60

[0668] Preparation of 2-{[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-ethylimidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0669]

[0670] Prepared according to the procedure described in Example 1 for the synthesis of 4-{5- [(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6-ethylimidazo[2,1- b][1,3,4]thiadiazol-2-yl}piperazine-1 -carboxylic acid tert-butyl ester using 2-oxa-5- azabicyclo[2.2.1]heptane instead of piperazine-1-carboxylic acid tert-butyl ester to give 2-{[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-ethylimidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. 1 H-NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.75 (m, 1H), 4.56-4.50 (m, 1H), 4.02 (m, 1H), 3.90 (m, 1H), 3.60 (s, 3H), 3.54 (m, 1H), 3.45 (m, 1H), 2.62 (q, J = 7.6 Hz, 2H), 2.05 (m, 2H), 1.30 (t, J = 7.6 Hz, 3H). MS (m / z): 482.2 [M+1].

[0671] Example 61

[0672] 2-{[6-ethyl-2-(6-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-3,6-diazabicyclo[3.1.1] octan-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0673]

[0674] Referring to Example 2, 2-{[6-ethyl-2-(6-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-3,6- diazabicyclo[3.1.1]octan-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile was prepared using tert-butyl 3,6-diazabicyclo[3.1.1] heptane-6-carboxylate instead of tert-butyl piperazine-1-carboxylate. 1 H-NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.69 (m, 1H), 4.40 (m, 1H), 4.28-4.24 (m, 1H), 4.08-4.04 (m, 1H), 3.92-3.85 (m, 3H), 3.81-3.75 (m, 2H), 3.62 (s, 3H), 3.48 (m, 2H), 3.09 (s, 2H), 2.82-2.76 (m, 1H), 2.62 (q, J = 7.6 Hz, 2H), 1.68 (m, 1H), 1.31 (t, J = 7.6 Hz, 3H). MS (m / z): 594.2 [M+1].

[0675] Example 62

[0676] 2-{[6-ethyl-2-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)hexahydropyrrolo[3,4-b]pyrrol- 5(1H)-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole- 5-carbonitrile

[0677]

[0678] Reference Example 2 was repeated using 3-tert-butoxycarbonylaminoazetidine instead of piperazine-1-carboxylic acid tert-butyl ester to give 2-{[6-ethyl-2-(3-((2-(3- hydroxyazetidin-1-yl)-2-oxoethyl)(methyl)amino)azetidin-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. 1 H-NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.69-4.62 (m, 1H), 4.40-4.33 (m, 1H), 4.31-4.23 (m, 2H), 4.06-3.98 (m, 1H), 3.91-3.84 (m, 1H), 3.64-3.57 (m, 1H), 3.60 (s, 3H), 3.55-3.49 (m, 1H), 3.18-3.10 (m, 2H), 3.08-3.0 (m, 2H), 2.82-2.75 (m, 1H), 2.67-2.56 (m, 4H), 2.27-2.18 (m, 1H), 2.03-1.96 (m, 1H), 1.29 (m, 3H). MS (m / z): 608.2 [M+1].

[0679] Example 63

[0680] Preparation of 2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)(methyl)amino)azetidin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0681]

[0682] Reference Example 2 was repeated using 3-tert-butoxycarbonylaminoazetidine instead of piperazine-1-carboxylic acid tert-butyl ester to give 2-{[6-ethyl-2-(3-((2-(3- hydroxyazetidin-1-yl)-2-oxoethyl)(methyl)amino)azetidin-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. 1H-NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 4.70 (m, 1H), 4.41 (m, 1H), 4.30-4.26 (m, 1H), 4.15 (m, 2H), 4.08-4.02 (m, 3H), 3.93-3.89 (m, 1H), 3.78 (m, 1H), 3.59 (s, 3H), 3.08 (s, 2H), 2.62 (q, J = 7.2 Hz, 2H), 2.34 (s, 3H), 1.30-1.28 (m, 3H). MS (m / z): 582.2 [M+1].

[0683] Example 64

[0684] Preparation of N-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]pyrrolidin-3-yl}-3-hydroxyazetidine-1- carboxamide

[0685]

[0686] Step 1) tert-Butyl (1-(6-ethyl-5-formamidylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydro pyrrol-3-yl)carbamate

[0687] Referring to the preparation method of tert-butyl 4-(6-ethyl-5-formamidylimidazo[2,1- b][1,3,4]thiadiazol-2-yl)piperazine-1-carboxylate in Example 1, tert-butyl (1-(6-ethyl-5- formamidylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3-yl)carbamate was prepared by replacing tert-butyl piperazine-1-carboxylate with 3-tert-butoxyamidotetrahydropyrrolidine. MS (m / z): 381.2 [M+1].

[0688] Step 2) tert-Butyl {1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}carbamate

[0689] tert-Butyl (1-(6-ethyl-5-formylaminoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)tetrahydropyrrol-3- yl)carbamate (300 mg, 0.79 mmol) was dissolved in DMF (3 mL), potassium tert-butoxide (256 mg, 2.28 mmol) was added, after stirring for 5 minutes, N-(2-bromo-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5- yl)formamide (181 mg, 0.76 mmol) was added, the reaction was allowed to warm to room temperature and stirred for 30 minutes, the reaction was complete by LC-MS. The reaction was poured into water, extracted with ethyl acetate (20 mL x 3), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give 260 mg of white solid, yield: 62%. MS (m / z): 555.2 [M+1].

[0690] Step 3) tert-Butyl {1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}carbamate

[0691] tert-Butyl {1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}carbamate (200 mg, 0.36 mmol) was dissolved in tetrahydrofuran (4 mL), cooled to -10 °C, potassium tert-butoxide (44 mg, 0.40 mmol) was added, after stirring for 10 minutes, iodomethane (62 mg, 0.43 mmol) was added; the reaction was allowed to warm to room temperature and stirred for 6 hours, the reaction was complete by LC-MS. The reaction was poured into water, extracted with ethyl acetate (20 mL x 3), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give 176 mg of white solid, yield: 86%. MS (m / z): 569.2 [M+1].

[0692] Step 4) 2-{[2-(3-Aminotetrahydropyrrol-1-yl)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0693] {1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]pyrrolidin-3-yl}-carbamic acid tert-butyl ester (176 mg, 0.36 mmol) was dissolved in 1,4-dioxane (2 mL), cooled to 0-5 °C, and 4N HCl / 1,4-dioxane (2 mL) was added dropwise. After 10 minutes, the reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction was complete by LC-MS. The solvent was evaporated, ethyl acetate (4 mL) was added and stirred for 30 minutes. The mixture was filtered, the filter cake was dissolved in methanol (5 mL), sodium bicarbonate (80 mg) was added and stirred for 30 minutes. The solvent was evaporated. The residue was dissolved in dichloromethane (5 mL), filtered, and the filtrate was dried over anhydrous sodium sulfate. The solvent was evaporated to give 140 mg of white solid, yield: 96%. MS (m / z): 469.2 [M+1].

[0694] Step 5) N-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]pyrrolidin-3-yl}-3-hydroxyazetidine-1- carboxamide

[0695] Referring to Example 30, N-{1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]pyrrolidin-3-yl}-3-hydroxyazetidine-1- carboxamide was prepared using 2-{[2-(3-aminotetrahydropyrrolidin-1-yl)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole- 5-carbonitrile instead of 2-{[6-ethyl-2-(3-(methylamino)tetrahydropyrrolidin-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. 1 H NMR (400 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 4.65 (m, 1H), 4.50 (m, 1H), 4.23 (m, 1H), 4.16 (m, 2H), 3.84-3.74 (m, 3H), 3.58-3.53 (m, 5H), 3.31 (m, 1H), 2.60 (m, 3H), 2.36 (s, 1H), 2.02 (m, 1H), 2.03 (m, 1H), 1.28 (m, 3H). MS (m / z): 568.2 [M+1].

[0696] Example 65

[0697] 2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)-3,3-dimethylpiperazin-l- yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile

[0698]

[0699] Reference Example 2 using 2,2-dimethylpiperazine-l-carboxylic acid tert-butyl ester instead of piperazine-l-carboxylic acid tert-butyl ester to give 2-{[6-ethyl-2-(4-(2-(3- hydroxyazetidin-l-yl)-2-oxoethyl)-3,3-dimethylpiperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol- 5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. 1 H NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.17 (m, 2H), 4.68 (m, 1H), 4.50 (m, 1H), 4.27 (m, 1H), 4.15 (m, 1H), 3.90 (m, 1H), 3.59 (s, 3H), 3.50 (m, 2H), 3.31 (m, 1H), 3.21 (m, 2H), 3.13 (m, 2H), 2.73 (m, 2H), 2.60 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H), 1.12 (s, 6H). MS (m / z): 610.2 [M+l].

[0700] Example 66

[0701] (R)-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)-2-methylpiperazin-l- yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile

[0702]

[0703] Reference Example 2 using (R)-3-methylpiperazine-l-carboxylic acid tert-butyl ester instead of piperazine-l-carboxylic acid tert-butyl ester to give (R)-2-{[6-ethyl-2-(4-(2-(3- hydroxyazetidin-l-yl)-2-oxoethyl)-2-methylpiperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5- yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. 1H NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 4.72 (m, 1H), 4.46 (m, 1H), 4.31 (m, 1H), 4.12 (m, 1H), 3.93 (m, 2H), 3.60 (s, 4H), 3.44 (m, 1H), 3.07 (m, 2H), 2.93 (m, 1H), 2.79 (m, 1H), 2.62 (m, 2H), 2.50 (m, 1H), 2.34 (m, 1H), 1.42 (m, 3H), 1.28 (m, 3H). MS (m / z): 596.2 [M+l].

[0704] Example 67

[0705] Preparation of (S)-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2- oxoethyl)-2-methylpiperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile

[0706]

[0707] (S)-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)-2- methylpiperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile was prepared according to the procedure described in Reference Example 2, using (S)-3-methylpiperazine-l-carboxylic acid tert-butyl ester instead of piperazine-l-carboxylic acid tert-butyl ester. 1 H NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 4.72 (m, 1H), 4.46 (m, 1H), 4.31 (m, 1H), 4.12 (m, 1H), 3.93 (m, 2H), 3.60 (s, 4H), 3.44 (m, 1H), 3.07 (m, 2H), 2.93 (m, 1H), 2.79 (m, 1H), 2.62 (m, 2H), 2.50 (m, 1H), 2.34 (m, 1H), 1.42 (m, 3H), 1.28 (m, 3H). MS (m / z): 596.2 [M+l].

[0708] Example 68

[0709] Preparation of (S)-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2- oxoethyl)-3-methylpiperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile

[0710]

[0711] Referring to Example 2, (S)-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2- oxoethyl)-3-methylpiperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared using (S)-2-methylpiperazine-l- carboxylic acid tert-butyl ester instead of piperazine-l-carboxylic acid tert-butyl ester. 1 H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.71 (m, 1H), 4.45 (m, 1H), 4.29 (m, 1H), 4.10 (m, 1H), 3.91 (m, 1H), 3.60 (m, 5H), 3.45-3.32 (m, 2H), 3.02-2.92 (m, 3H), 2.76 (m, 1H), 2.66-2.58 (m, 4H), 1.30 (t, J = 7.6 Hz, 3H), 1.14 (d, J = 6.0 Hz, 3H). MS (m / z): 596.2 [M+l].

[0712] Example 69

[0713] Preparation of (R)-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)-3- methylpiperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0714]

[0715] Referring to Example 2, (R)-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2- oxoethyl)-3-methylpiperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared using (R)-2-methylpiperazine-l- carboxylic acid tert-butyl ester instead of piperazine-l-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.71 (m, 1H), 4.46 (m, 1H), 4.30 (m, 1H), 4.11 (m, 1H), 3.91 (m, 1H), 3.60 (m, 5H), 3.45-3.32 (m, 2H), 3.02-2.92 (m, 3H), 2.76 (m, 1H), 2.66-2.58 (m, 3H), 2.47 (m, 1H), 1.30 (t, J = 7.6 Hz, 3H), 1.15 (d, J = 5.6 Hz, 3H). MS (m / z): 596.2 [M+l].

[0716] Example 70

[0717] Preparation of 2-{[6-ethyl-2-(8-(2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile

[0718]

[0719] Reference Example 2 was followed using tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate in place of tert-butyl piperazine-l-carboxylate to give 2-{[6-ethyl-2-(8-(2-(3- hydroxyazetidin-l-yl)-2-oxoethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[2,l- b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile. 1 H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.71 (m, 1H), 4.46 (m, 1H), 4.30 (m, 1H), 4.11 (m, 1H), 3.91 (m, 1H), 3.60 (m, 5H), 3.45-3.32 (m, 2H), 3.02-2.92 (m, 3H), 2.76 (m, 1H), 2.66-2.58 (m, 3H), 2.47 (m, 1H), 1.30 (t, J = 7.6 Hz, 3H), 1.15 (d, J = 5.6 Hz, 3H). MS (m / z): 596.2 [M+l].

[0720] Example 71

[0721] 2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-4,7-diazaspiro[2.5]octan-7- yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile

[0722]

[0723] 2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-4,7-diazaspiro[2.5]octan-7- yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile was prepared according to the procedure described in Reference Example 2, using tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate instead of tert-butyl piperazine-1- carboxylate. 1 H-NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.69 (m, 1H), 4.41-4.36 (m, 1H), 4.30-4.26 (m, 1H), 4.05-4.02 (m, 1H), 3.91-3.88 (m, 1H), 3.59 (s, 3H), 3.50-3.40 (m, 4H), 3.25 (s, 2H), 3.16 (m, 2H), 2.62 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H), 0.81 (m, 2H), 0.68 (m, 2H). MS (m / z): 608.4 [M+1].

[0724] Example 72

[0725] 2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-3,5-dimethylpiperazin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile

[0726]

[0727] 2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-3,5-dimethylpiperazin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5- carbonitrile was prepared according to the procedure described in Reference Example 2, using tert-butyl cis-3,5-dimethylpiperazine-1-carboxylate instead of tert-butyl piperazine-1- carboxylate. 1H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.71 (m, 1H), 4.41 (m, 1H), 4.28 (m, 1H), 4.05 (m, 1H), 3.90 (m, 1H), 3.60 (m, 5H), 3.43 (m, 2H), 3.28 (m, 2H), 2.88 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.30 (m, 3H), 1.15 (m, 6H). MS (m / z): 610.3 [M + 1].

[0728] Example 73

[0729] Preparation of trans-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2- oxoethyl)-3,5-dimethylpiperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile

[0730]

[0731] Referring to Example 2, trans-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2- oxoethyl)-3,5-dimethylpiperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared using trans-3,5-dimethylpiperazine- 1-carboxylic acid tert-butyl ester instead of piperazine- 1-carboxylic acid tert-butyl ester. 1 H-NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.75-4.67 (m, 1H), 4.57-4.47 (m, 1H), 4.34-4.27 (m, 1H), 4.22-4.12 (m, 1H), 3.94-3.88 (m, 1H), 3.60 (m, 3H), 3.58-3.50 (m, 2H), 3.45-3.36 (m, 1H), 3.24-3.15 (m, 2H), 3.14-3.03 (m, 3H), 2.64 (m, 2H), 1.28 (m, 3H), 1.10 (m, 6H). MS (m / z): 610.3 [M + 1].

[0732] Example 74

[0733] 2-{[6-ethyl-2-((2S,5S)-4-(2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)-2,5- dimethylpiperazin- 1 -yl)imidazo[2, 1 -b] [ 1,3,4]thiadiazol-5-yl](methyl)amino} -4- (4-fluorophenyl)thiazole-5-carbonitrile

[0734]

[0735] 2-{[6-ethyl-2-((2S,5S)-4-(2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)-2,5- dimethylpiperazin- 1 -yl)imidazo[2, 1 -b] [ 1,3,4]thiadiazol-5-yl](methyl)amino} -4- (4-fluorophenyl)thiazole-5-carbonitrile was prepared according to the procedure of Reference Example 2, using trans-(2S,5S)-2,5-dimethylpiperazine-l-carboxylic acid tert-butyl ester instead of piperazine- 1 -carboxylic acid tert-butyl ester. 1 H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.72 (m, 1H), 4.48 (m, 1H), 4.30 (m, 1H), 4.13 (m, 1H), 3.91 (m, 2H), 3.60 (s, 3H), 3.48 (m, 2H), 3.03 (m, 1H), 2.92 (m, 1H), 2.74 (m, 2H), 2.61 (m, 3H), 2.45 (m, 1H), 1.40 (m, 3H), 1.30 (t, J = 7.6 Hz, 3H), 1.16 (m, 3H). MS (m / z): 610.2 [M+l].

[0736] Example 75

[0737] 2-{[6-ethyl-2-((2S,5S)-4-(2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)-2,5- dimethylpiperazin- 1 -yl)imidazo[2, 1 -b] [ 1,3,4]thiadiazol-5-yl](methyl)amino} -4- (4-fluorophenyl)thiazole-5-carbonitrile

[0738]

[0739] 2-{[6-ethyl-2-((2S,5S)-4-(2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)-2,5- dimethylpiperazin- 1 -yl)imidazo[2, 1 -b] [ 1,3,4]thiadiazol-5-yl](methyl)amino} -4- (4-fluorophenyl)thiazole-5-carbonitrile was prepared according to the procedure of Reference Example 2, using trans-(2S,5S)-2,5-dimethylpiperazine-l-carboxylic acid tert-butyl ester instead of piperazine- 1 -carboxylic acid tert-butyl ester.1 H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.70 (m, 1H), 4.47 (m, 1H), 4.28 (m, 1H), 4.11 (m, 1H), 3.91 (m, 2H), 3.60 (s, 3H), 3.47 (m, 2H), 3.06-2.90 (m, 3H), 2.75 (m, 2H), 2.60 (m, 3H), 1.40 (m, 3H), 1.29 (m, 3H), 1.16 (m, 3H). MS (m / z): 610.3 [M+1].

[0740] Example 76

[0741] Preparation of trans-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2- oxoethyl)-2,5-dimethylpiperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile

[0742]

[0743] Reference Example 2 was followed using trans-2,5-dimethylpiperazine-l- carboxylic acid tert-butyl ester in place of piperazine-l-carboxylic acid tert-butyl ester to give trans-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)-2,5- dimethylpiperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile. 1 H NMR (400 MHz, CDC13) δ: 8.17 (m, 2H), 7.18 (m, 2H), 4.72 (m, 1H), 4.47 (m, 1H), 4.30 (m, 1H), 4.12 (m, 1H), 3.93 (m, 2H), 3.60 (s, 4H), 3.36 (m, 1H), 3.19-3.06 (m, 3H), 2.94 (m, 1H), 2.70-2.59 (m, 3H), 2.49 (m, 1H), 1.41 (m, 3H), 1.30 (t, J = 7.6 Hz, 3H), 1.07 (m, 3H). MS (m / z): 610.2 [M+1].

[0744] Example 77

[0745] 2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,3-dimethylpiperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0746]

[0747] 2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,3-dimethylpiperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared according to Reference Example 2, using tert-butyl 2,3-dimethylpiperazine-1 -carboxylate instead of tert-butyl piperazine-1 -carboxylate. 1 H NMR (400 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 4.71 (m, 1H), 4.48 (m, 1H), 4.30 (m, 1H), 4.16 (m, 1H), 3.97-3.90 (m, 2H), 3.65-3.58 (m, 4H), 3.41 (s, 1H), 3.15 (m, 2H), 2.92 (m, 1H), 2.77 (m, 1H), 2.56 (m, 3H), 1.43 (m, 3H), 1.28 (m, 3H), 1.09 (m, 3H). MS (m / z): 610.23 [M+1].

[0748] Example 78

[0749] 2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,3-dimethylpiperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0750]

[0751] 2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-2,3-dimethylpiperazin-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared according to Reference Example 21, using 2-chloro-1 -(3-hydroxyazetidin-1 -yl)propan-1 -one instead of 2-chloro-1 -(3-hydroxyazetidin-1 -yl)ethanone. 1H NMR (400 MHz, CDC13) δ: 8.15 (m, 2H), 7.16 (m, 2H), 4.67 (m, 1H), 4.57 (m, 1H), 4.36 (m, 1H), 4.26 (m, 2H), 4.01 (m, 1H), 3.89 (m, 1H), 3.64-3.50 (m, 5H), 3.44 (m, 1H), 3.30 (m, 1H) 2.60 (q, J = 7.6 Hz, 2H), 2.30-2.21 (m, 4H), 2.03 (m, 2H), 1.28 (m, 3H), 1.19 (m, 3H). MS (m / z): 610.33 [M+1].

[0752] Example 79

[0753] Preparation of 2-{[6-ethyl-2-(4-(3-hydroxyazetidine-l-carbonyl)piperidin-l- yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole- 5-carbonitrile

[0754]

[0755] Step 1) Methyl l-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,l-b][l,3,4]thiadiazol-2-yl}piperidine-4-carboxylate

[0756] Methyl l-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,l-b][l,3,4]thiadiazol-2-yl}piperidine-4-carboxylate was prepared according to the procedure described in Example 1 for the preparation of tert-butyl 4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,l-b][l,3,4]thiadiazol-2-yl}piperazine-l-carboxylate, using methyl piperidine-4-carboxylate instead of tert-butyl piperazine-l-carboxylate. MS (m / z): 526.2 [M+1].

[0757] Step 2) l-{5-[(5-Cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,l-b][l,3,4]thiadiazol-2-yl}piperidine-4-carboxylic acid

[0758] Methyl 1-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}piperidine-4-carboxylate (509 mg, 0.97 mmol) was dissolved in tetrahydrofuran (3 mL) and water (2 mL), and lithium hydroxide (122 mg, 2.91 mmol) was added. The reaction was stirred at room temperature for 3 hours, and was complete by LC-MS. The reaction was quenched with water (6 mL), and the pH was adjusted to about 3 with 1 N aqueous hydrogen chloride. A white solid precipitated, which was filtered and dried under vacuum to give 421 mg of a white solid in 85% yield. MS (m / z): 512.2 [M+1].

[0759] Step 3) 2-{[6-Ethyl-2-(4-(3-hydroxyazetidine-1-carbonyl)piperidin-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0760] Methyl 1-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}piperidine-4-carboxylate (509 mg, 0.97 mmol) was dissolved in tetrahydrofuran (3 mL) and water (2 mL), and lithium hydroxide (122 mg, 2.91 mmol) was added. The reaction was stirred at room temperature for 3 hours, and was complete by LC-MS. The reaction was quenched with water (6 mL), and the pH was adjusted to about 3 with 1 N aqueous hydrogen chloride. A white solid precipitated, which was filtered and dried under vacuum to give 421 mg of a white solid in 85% yield. MS (m / z): 512.2 [M+1]. 1 H NMR (400 MHz, CDC13) δ: 8.14 (m, 2H), 7.16 (m, 2H), 4.71 (m, 1H), 4.39 (m, 1H), 4.25 (m, 1H), 4.04 (m, 1H), 3.94-3.80 (m, 3H), 3.58 (s, 3H), 3.11 (m, 2H), 2.58 (q, J = 7.6 Hz, 2H), 2.42 (m, 1H), 1.94-1.75 (m, 4H), 1.28 (m, 3H). MS (m / z): 567.4 [M+1].

[0761] Example 80

[0762] Preparation of (R)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2- oxoethyl)amino)tetrahydropyran-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile

[0763]

[0764] Step 1) 2-{[2-bromo-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0765] N-(2-bromo-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)formamide (525 mg, 1.91 mmol) was dissolved in THF (8 mL), cooled in ice bath, added 60% sodium hydride (229 mg, 5.73 mmol), stirred for 15 min, added 2-chloro-4-(4-fluorophenyl)thiazole-5- carbonitrile (454 mg, 1.91 mmol) in tetrahydrofuran (3 mL) dropwise. The reaction was allowed to warm to room temperature for 30 min, monitored by TLC, added iodomethane (542 mg, 3.82 mmol), continued to react at room temperature for 2 h. The reaction was monitored by LC-MS, quenched by water dropwise, added water (30 mL), extracted with ethyl acetate (30 mL x 3), combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to give 603 mg of white solid, yield: 68%.

[0766] Step 2) (R)-tert-butyl {1-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]tetrahydropyran-3-yl}carbamate

[0767] (R)-3-tert-butoxycarbonylpyrrolidine (100 mg, 0.537 mmol) was dissolved in DMF (6 mL), potassium carbonate (222 mg, 1.61 mmol) and 2-{[2-bromo-6-ethylimidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile (248 mg, 0.537 mmol) were added. The reaction was heated to 65 °C for 3 hours, and was complete by LC-MS. The reaction was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3), the organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1.5: 1) to give 275 mg of white solid, yield: 90%.

[0768] (R)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)amino)pyrrolidin-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0769] (R)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)amino)pyrrolidin-1-yl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared according to the procedure described in Example 2, using (R)-{1-[5-((5-cyano-4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino)-6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl]pyrrolidin-3- yl}formic acid tert-butyl ester instead of 4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]- 6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}piperazine-1-carboxylic acid tert-butyl ester. 1 HNMR (400 MHz, CDC13) δ: 8.15 (m, 2H), 7.18 (m, 2H), 4.70 (m, 1H), 4.30 (m, 2H), 3.99 (m, 1H), 3.91 (m, 1H), 3.64-3.46 (m, 7H), 3.33-3.16 (m, 3H), 2.60 (q, J = 7.6 Hz, 2H), 2.22 (m, 1H), 1.99 (m, 2H), 1.28 (m, 3H). MS (m / z): 582.2 [M+1].

[0770] Example 81

[0771] Preparation of (S)-4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]- 6-ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1-(2-(3-hydroxyazetidin-1-yl)-2- oxoethyl)piperazine-2-carboxylic acid methyl ester

[0772]

[0773] Referring to Example 80, (S)-4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}-1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazine- 2-carboxylic acid methyl ester was prepared using (S)-1-Boc-2-piperazinecarboxylic acid methyl ester instead of (R)-3-tert-butoxycarbonylamino tetrahydropyrrole. 1 H NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 4.69 (m, 1H), 4.42 (m, 1H), 4.28 (m, 1H), 4.07 (m, 1H), 3.89 (m, 2H), 3.76-3.64 (m, 6H), 3.59 (s, 3H), 3.47-3.36 (m, 3H), 3.21 (m, 1H), 2.78 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 1.29 (d, J = 7.6 Hz, 3H). MS (m / z): 640.2 [M+1].

[0774] Example 82

[0775] Preparation of (S)-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-3- (hydroxymethyl)piperazin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile

[0776]

[0777] Methyl (S)-4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2, 1-b] [1, 3, 4]thiadiazol-2-yl}-1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazine- 2-carboxylate (100 mg, 0.14 mmol) was dissolved in tetrahydrofuran (1 mL) and ethanol (3 mL), lithium bromide (4 mg, 0.47 mmol) and sodium borohydride (16 mg, 0.48 mmol) were added. After stirring at room temperature for 3 hours, it was concentrated in vacuo and purified by thick plate to give 10 mg of white solid, yield: 11%. MS (m / z): 626.2 [M+1].

[0778] Example 83

[0779] Preparation of (S)-4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2, 1-b] [1, 3, 4]thiadiazol-2-yl}-1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-N- methylpiperazine-2-carboxamide

[0780]

[0781] 1) (S)-4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2, 1-b] [1, 3, 4]thiadiazol-2-yl}-1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazine- 2-carboxylic acid

[0782] Methyl (S)-4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2, 1-b] [1, 3, 4]thiadiazol-2-yl}-1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazine- 2-carboxylate (50 mg, 0.07 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL), lithium hydroxide (5 mg, 0.12 mmol) was added. After stirring at room temperature for 3 hours, it was concentrated in vacuo, water (3 mL) was added, pH was adjusted to about 5 with 1 N hydrochloric acid, filtered and dried to give 47 mg of off-white solid. MS (m / z): 626.2 [M+1].

[0783] 2) (S)-4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2, 1-b] [1, 3, 4]thiadiazol-2-yl}-1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-N- methylpiperazine-2-carboxamide

[0784] (S)-4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2, 1 -b] [ 1,3,4]thiadiazol-2-yl} - 1 -(2-(3 -hydroxyazetidin- 1 -yl)-2- oxoethyl)piperazine-2-carboxylic acid (34 mg, 0.05 mmol) was dissolved in tetrahydrofuran (4 mL), HATU (23 mg, 0.06 mmol) and triethylamine (0.02 mL, 0.15 mmol) were added and stirred for 15 min before methylamine hydrochloride (5.5 mg, 0.08 mmol) was added. Stirred at room temperature for 4 h, after the reaction was complete by LC-MS, the solvent was evaporated and purified by thick prep plate to give 30 mg of white solid, yield: 89%. MS (m / z): 639.2 [M+1].

[0785] Example 84

[0786] Preparation of (R)-4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2, 1 -b] [ 1,3,4]thiadiazol-2-yl} - 1 -(2-(3 -hydroxyazetidin- 1 -yl)-2- oxoethyl)piperazine-2-carboxylic acid methyl ester

[0787]

[0788] Referring to Example 80, (R)-4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2, 1 -b] [ 1,3,4]thiadiazol-2-yl} - 1 -(2-(3 -hydroxyazetidin- 1 -yl)-2- oxoethyl)piperazine-2-carboxylic acid methyl ester was prepared using (R)-1-Boc-2- piperazinecarboxylic acid methyl ester instead of (R)-3-tert-butoxyamidotetrahydropyrrole. 1 H NMR (400 MHz, CDC13) δ: 8.16 (m, 2H), 7.18 (m, 2H), 4.70 (m, 1H), 4.42 (m, 1H), 4.30 (m, 1H), 4.08 (m, 1H), 3.89 (m, 2H), 3.76-3.64 (m, 6H), 3.59 (s, 3H), 3.46-3.36 (m, 3H), 3.22 (m, 1H), 2.79 (m, 2H), 2.60 (q, J = 7.6 Hz, 2H), 1.29 (d, J = 7.6 Hz, 3H). MS (m / z): 640.2 [M+1].

[0789] Example 85

[0790] (R)-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)-3- (hydroxymethyl)piperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile

[0791]

[0792] (R)-2-{[6-ethyl-2-(4-(2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)-3- (hydroxymethyl)piperazin-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared according to Reference Example 82, using (R)-methyl 1-Boc-2-piperazinecarboxylate instead of (S)-methyl 1-Boc-2- piperazinecarboxylate. MS (m / z): 612.2 [M+l].

[0793] Example 86

[0794] (R)-2-{[6-2-((benzyloxy)ethyl)-2-(3-((2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)(methyl)amino)tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile

[0795]

[0796] Step 1) 6-[2-(benzyloxy)ethyl]-2-bromo-N-(tert-butyl)imidazo[2,l- b][l,3,4]thiadiazol-5-amine

[0797] Dissolve 5-bromo-l,3,4-thiadiazol-2-amine (4.7 g, 26.26 mmol) in n-butanol (60 mL), add 3-(benzyloxy)propanal (6.9 g, 42.07 mmol), stir at room temperature for 10 minutes, then cool to 0 °C, add magnesium chloride (1.28 g, 13.47 mmol) and tert-butyl isocyanide (2.28 g, 27.47 mmol). Gradually raise to 70 °C for reaction, after 5 hours, detect the reaction complete by LC-MS. Spin dry the reaction liquid, add water (60 mL), then extract with ethyl acetate (60 mL x 2), combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, spin dry, purify by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain 4.1 g of oil, yield: 38%. MS (m / z): 409.1, 411.1 [M+l].

[0798] Step 2) N-{6-[2-(benzyloxy)ethyl]-2-bromoimidazo[2,1-b][1,3,4]thiadiazol-5- yl}acetamide

[0799] N-{6-[2-(benzyloxy)ethyl]-2-bromoimidazo[2,1-b][1,3,4]thiadiazol-5-yl}acetamide (580 mg, 1.472 mmol) was dissolved in tetrahydrofuran (15 mL) under nitrogen protection, and 60% NaH (151 mg, 3.77 mmol) was added after cooling with ice water bath. After stirring for 15 minutes, 2-chloro-4-(4-fluorophenyl)thiazole-5- carbonitrile (324 mg, 1.36 mmol) in tetrahydrofuran (3 mL) was added dropwise. After the addition was completed, the reaction was allowed to proceed at room temperature. After 30 minutes, the reaction was monitored to be complete by thin layer chromatography, and iodomethane (321 mg, 2.26 mmol) was added. After the reaction was allowed to proceed for 2 hours, the reaction was quenched by dropwise addition of water, and water (20 mL) was added. The organic layer was extracted with ethyl acetate (20 mL x 3), and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 481 mg of white solid with a yield of 85%. MS (m / z): 569.1, 571.1 [M+1].

[0800] Step 3) 2-{[6-(2-(benzyloxy)ethyl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0801] N-{6-[2-(benzyloxy)ethyl]-2-bromoimidazo[2,1-b][1,3,4]thiadiazol-5-yl}acetamide (580 mg, 1.472 mmol) was dissolved in tetrahydrofuran (15 mL) under nitrogen protection, and 60% NaH (151 mg, 3.77 mmol) was added after cooling with ice water bath. After stirring for 15 minutes, 2-chloro-4-(4-fluorophenyl)thiazole-5- carbonitrile (324 mg, 1.36 mmol) in tetrahydrofuran (3 mL) was added dropwise. After the addition was completed, the reaction was allowed to proceed at room temperature. After 30 minutes, the reaction was monitored to be complete by thin layer chromatography, and iodomethane (321 mg, 2.26 mmol) was added. After the reaction was allowed to proceed for 2 hours, the reaction was quenched by dropwise addition of water, and water (20 mL) was added. The organic layer was extracted with ethyl acetate (20 mL x 3), and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 481 mg of white solid with a yield of 85%. MS (m / z): 569.1, 571.1 [M+1].

[0802] Step 4) (R)-tert-butyl {1-[6-(2-(benzyloxy)ethyl)-5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[2,1-b][1,3,4]thiadiazol-2-yl]pyrrolidin-3-yl}(methyl)carbamate

[0803] (R)-3-tert-butoxycarbonylpyrrolidine (149 mg, 0.75 mmol) was dissolved in DMF (6 mL), potassium carbonate (295 mg, 2.14 mmol) and 2-{[6-(2-(benzyloxy)ethyl)-2-bromoimidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile (481 mg, 0.85 mmol) were added. The reaction was heated to 70 °C for 3 hours, and was complete by LC-MS. The reaction was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3), the organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to give 409 mg of white solid, yield: 70%. MS (m / z): 689.3 [M+1].

[0804] (R)-2-{[6-2-((BENZYLOXY)ETHYL)-2-(3-((2-(3-HYDROXYAZETIDIN-1-YL)-2-OXOETHYL)(METHYL)AMINO)PYRROLIDIN-1-YL)IMIDAZO[2,1-B][1,3,4]THIADIAZOL-5-YL](METHYL)AMINO}-4-(4-FLUOROPHENYL)THIAZOLE-5-CARBONITRILE

[0805] (R)-2-{[6-2-((BENZYLOXY)ETHYL)-2-(3-((2-(3-HYDROXYAZETIDIN-1-YL)-2-OXOETHYL)(METHYL)AMINO)PYRROLIDIN-1-YL)IMIDAZO[2,1-B][1,3,4]THIADIAZOL-5-YL](METHYL)AMINO}-4-(4-FLUOROPHENYL)THIAZOLE-5-CARBONITRILE was prepared according to the procedure described in Reference Example 2, using (R)-{1-[6-(2-(benzyloxy)ethyl)-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[2,1-b][1,3,4]thiadiazol-2-yl]pyrrolidin-3-yl}(methyl)carbamic acid tert-butyl ester instead of 4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2,1-b][1,3,4]thiadiazol-2-yl}piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, CDC13) δ: 8.13 (m, 2H), 7.30-7.24 (m, 5H), 7.16 (m, 2H), 4.65 (m, 1H), 4.51 (s, 2H), 4.40 (m, 1H), 4.26 (m, 1H), 4.06 (m, 1H), 3.89 (m, 1H), 3.79 (m, 2H), 3.67-3.52 (m, 5H), 3.43 (m, 2H), 3.33 (m, 1H), 3.16 (m, 2H), 2.87 (m, 2H), 2.38 (s, 3H), 2.24 (m, 1H), 2.09 (m, 1H). MS (m / z): 702.6 [M+l].

[0806] Example 87

[0807] Preparation of (R)-4-(4-fluorophenyl)-2-{[2-(3-((2-(3-hydroxyazetidin-l-yl)-2- oxoethyl)(methyl)amino)tetrahydropyrrol-l-yl)-6-(2-hydroxyethyl)imidazo[2,l- b][l,3,4]thiadiazol-5-yl](methyl)amino}thiazole-5-carbonitrile

[0808]

[0809] (R)-2-{[6-2-((Benzyl oxy)ethyl)-2-(3-((2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)(methyl)amino)tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile (50 mg, 0.071 mmol) was dissolved in dichloromethane (10 mL), stirred under nitrogen protection, cooled to 0-5 °C, then added titanium tetrachloride (32 mg, 0.168 mmol) dropwise, stirred for 10 minutes after the addition was completed, then raised to room temperature for 30 minutes, and detected by LC-MS to determine that the reaction was complete. 1 N HCl (1 mL) was added to quench the reaction, stirred for 15 minutes, then the pH value was adjusted to about 10 with saturated sodium bicarbonate solution, filtered, extracted with dichloromethane (20 mL x 3), combined organic layers, dried over anhydrous sodium sulfate, rotary evaporated, purified by thick preparation plate (dichloromethane:methanol = 12:1) to obtain 33 mg of white solid, yield: 77%. 1H NMR (400 MHz, CDC13) δ: 8.13 (m, 2H), 7.15 (m, 2H), 4.68 (m, 1H), 4.40 (m, 1H), 4.27 (m, 1H), 4.08 (m, 1H), 3.91 (m, 3H), 3.68-3.59 (m, 6H), 3.47 (s, 2H), 3.24 (m, 2H), 2.78 (m, 2H), 2.47 (s, 3H), 2.01 (m, 1H), 2.27 (m, 1H), 2.14 (m, 1H). MS (m / z): 612.68 [M+1].

[0810] Example 88

[0811] Preparation of (R)-4-(4-fluorophenyl)-2-{[2-(3-((2-(3-hydroxyazetidin-1-yl)-2- oxoethyl)(methyl)amino)tetrahydropyrrol-1-yl)-6-(2-methoxyethyl)imidazo[2,1- b][1,3,4]thiadiazol-5-yl](methyl)amino}thiazole-5-carbonitrile

[0812]

[0813] Step 1) 2-{[2-bromo-6-(2-hydroxyethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0814] Step 1) 2-{[2-bromo-6-(2-hydroxyethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0815] Step 2) (R)-tert-buty\ { 1 -5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]- 6-(2-methoxyethyl)imidazo[2, 1 -b] [ 1,3,4]thiadiazol-2-yl} pyrrolidin-3-yl} (methyl)carbamate

[0816] (R)-3-tert-butoxyamidopyrrolidine (90 mg, 0.45 mmol) was dissolved in DMF (6 mL), potassium carbonate (186 mg, 1.35 mmol) and 2-{[2-bromo-6-(2-hydroxyethyl)imidazo[2, 1 - b][ 1,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile (140 mg, 0.293 mmol) were added. The reaction was heated to 70 °C for 3 hours and was complete by LC-MS. After cooling in an ice water bath, 60% NaH (28 mg, 0.68 mmol) was added and the reaction was stirred for 10 minutes. Methyl iodide (128 mg, 0.9 mmol) was added and the reaction was stirred for 3 hours and was complete by LC-MS. The reaction was poured into water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1 :2) to give 110 mg of a white solid. Yield: 61%.

[0817] Step 3) (R)-4-(4-fluorophenyl)-2-{[2-(3-((2-(3-hydroxyazetidin- 1 -yl)-2-oxoethyl)(methyl)amino)pyrrolidin- 1 -yl)-6-(2-methoxyethyl)imidazo[2, 1 - b][ 1,3,4]thiadiazol-5-yl](methyl)amino}thiazole-5-carbonitrile

[0818] Referring to Example 2, (R)-4-(4-fluorophenyl)-2-{[2-(3-((2-(3-hydroxyazetidin- 1 -yl)-2-oxoethyl)(methyl)amino)pyrrolidin- 1 -yl)-6-(2-methoxyethyl)imidazo[2, 1 - b][ 1,3,4]thiadiazol-5-yl](methyl)amino}thiazole-5-carbonitrile was prepared using (R)-tert-butyl { 1 -5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]- 6-(2-methoxyethyl)imidazo[2, 1 -b] [ 1,3,4]thiadiazol-2-yl} pyrrolidin-3-yl} (methyl)carbamate instead of tert-butyl 4-{5-[(5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino]-6- ethylimidazo[2, 1 -b][ 1,3,4]thiadiazol-2-yl}piperazine- 1 -carboxylate. 1H NMR (400 MHz, CDC13) δ: 8.15 (m, 2H), 7.16 (m, 2H), 4.68 (m, 1H), 4.40 (m, 1H), 4.28 (m, 1H), 4.08 (m, 1H), 3.91 (m, 1H), 3.70-3.59 (m, 8H), 3.46 (s, 2H), 3.33-3.28 (m, 5H), 2.83 (m, 2H), 2.51 (s, 3H), 2.28 (m, 1H), 2.18 (m, 1H). MS (m / z): 626.28 [M+1].

[0819] Example 89

[0820] Preparation of (R)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2- oxoethyl)amino)tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile

[0821]

[0822] (R)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2- oxoethyl)amino)tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile (40 mg, 0.069 mmol) was dissolved in acetonitrile, iodomethane (22 mg, 0.14 mmol) and potassium carbonate (29 mg, 0.21 mmol) were added and heated to 75 °C overnight. The reaction was cooled, filtered, spun dry and purified by thick plate (dichloromethane:methanol = 20:1) to give 26 mg of white solid, yield: 62%. 1 H NMR (400 MHz, CDC13) δ: 8.15 (m, 2H), 7.16 (m, 2H), 4.68 (m, 1H), 4.40 (m, 1H), 4.28 (m, 1H), 4.08 (m, 1H), 3.91 (m, 1H), 3.70-3.59 (m, 8H), 3.46 (s, 2H), 3.33-3.28 (m, 5H), 2.83 (m, 2H), 2.51 (s, 3H), 2.28 (m, 1H), 2.18 (m, 1H). MS (m / z): 626.28 [M+1].

[0823] Example 90

[0824] (R)-2-{[6-ethyl-2-(3-((cyclopropylmethyl)(2-(3-hydroxyazetidin-l-yl)-2- oxoehtyl)amino)tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}- 4-(4-fluorophenyl)thiazole-5-carbonitrile

[0825]

[0826] Referring to Example 89, (R)-2-{[6-ethyl-2-(3-((cyclopropylmethyl)(2-(3- hydroxyazetidin-l-yl)-2-oxoethyl)amino)tetrahydropyrrol-l-yl)imidazo[2,l- b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4-fluorophenyl)thiazole-5-carbonitrile was prepared using bromomethylcyclopropane instead of iodoethane. 1 H NMR (400 MHz, CDC13) δ: 8.15 (m, 2H), 7.16 (m, 2H), 4.69 (m, 1H), 4.42 (m, 1H), 4.26 (m, 1H), 4.09 (m, 1H), 3.89 (m, 1H), 3.70-3.42 (m, 10H), 2.72 (m, 2H), 2.59 (m, 2H), 2.27 (m, 2H), 1.28 (m, 3H), 0.93 (m, 1H), 0.59 (m, 2H), 0.20 (m, 2H). MS (m / z): 636.3 [M+l].

[0827] Example 91

[0828] (R)-N-{l-[5-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6- ethylimidazo[2,l-b][l,3,4]thiadiazol-2-yl]tetrahydropyrrol-3-yl}-N-(2-(3- hydroxyazetidin-l-yl)-2-oxoethyl)formamide

[0829]

[0830] (R)-2-{[6-ethyl-2-(3-((2-(3-hydroxyazetidin-l-yl)-2-oxoethyl)amino) tetrahydropyrrol-l-yl)imidazo[2,l-b][l,3,4]thiadiazol-5-yl](methyl)amino}-4-(4- fluorophenyl)thiazole-5-carbonitrile (40 mg, 0.069 mmol) was dissolved in dichloromethane (3 mL), formic acid (9.5 mg, 0.21 mmol), HATU (80 mg, 0.21 mmol) and triethylamine (30 mg, 0.3 mmol) were added, and the reaction was allowed to proceed at room temperature for 2 days. The reaction was poured into water (10 mL), extracted with dichloromethane (10 mL x 3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification was performed by thick plate (dichloromethane:methanol = 20: 1) to obtain 23 mg of a white solid, yield: 55%. 1 H NMR (400 MHz, CDC13) δ: 12.05 (br, 1H), 8.15 (m, 2H), 7.18 (m, 2H), 4.70 (m, 1H), 4.48 (m, 1H), 4.28 (m, 1H), 4.14 (m, 1H), 3.92 (m, 1H), 3.84-3.74 (m, 2H), 3.66-3.51 (m, 6H), 3.12 (m, 2H), 2.61 (m, 2H), 2.41-2.34 (m, 2H), 1.30 (m, 3H). MS (m / z): 610.2 [M+l]. Biological test

[0831] In vitro assay: screening of enzyme activity with LPC as substrate

[0832] Principle: The lysoPLD enzyme activity can hydrolyze the substrate lysophosphatidylcholine (LPC) to generate lysophosphatidic acid (LPA) and choline. Choline is oxidized to H202 by choline oxidase. In the presence of horseradish peroxidase (HRP), Amplex Red reagent reacts with H202 in a 1:1 stoichiometric ratio to form a strong fluorescent product for fluorescence quantitative detection.

[0833] Experimental procedure: Test compounds were dissolved in DMSO to make 10 mM stock solution, and diluted with DMSO to make 3-fold gradient dilution, starting concentration 10 mM, 10 concentration points. Mixed solution 1 with final concentration of 2 ng / μl ATX, 2 U / ml HRP and 0.2 U / ml choline oxidase was prepared in reaction buffer solution. 20 μl of mixed solution 1 was added to each well of the experimental plate, and the compound diluted with DMSO was transferred into the experimental plate by Echo 550 at 10 nl / well. Mixed solution 2 with final concentration of 60 mM LPC and 400 uM Amplex Red was prepared in reaction buffer solution, and 20 μl of mixed solution 2 was added to each well of the experimental plate. After sample addition, the experimental plate was shaken on a plate shaker for 30 s, and incubated at room temperature for 30 min. The fluorescence signal was read by Envision at excitation 530 nm and emission 590 nm. The inhibition rate of the enzyme reaction by the compound was calculated according to the fluorescence ratio, and the IC 50 value of the compound was calculated by software analysis, see Table 1.

[0834] Table 1 ATX inhibition activity analysis of the compound of the present application with LPC as substrate

[0835] +: > 1000 nM; ++: 500-1000 nM; +++: 100-500 nM; ++++: 0.01-100 nM

[0836]

[0837]

[0838] Note: ND: not tested

[0839] From Table 1, it can be seen that the compound of the present application has good ATX inhibition activity, and the IC 50 value of most of the compounds is less than 500 nM, even less than 100 nM.

[0840] In vitro assay: screening of LPA detection activity in human plasma

[0841] Principle: LPC existing in blood plasma is used as substrate, LPA 18:2 is quantitatively analyzed and detected by LC / MS / MS (LPA 17:0 is used as internal standard), and the residual activity percentage is obtained from the generation amount of LPA 18:2 and the generation amount in the absence of the test compound at different concentration points of the test compound, and the IC 50 value is calculated.

[0842] Experimental procedure: The blank plasma was derived from at least 6 individual human mixed blank plasma, the test compound was diluted from stock solution with dilution 3 times gradient, and 8 series of concentration working solutions (including zero point) were prepared. 10 μL of the thawed blank plasma sample was taken, and ice methanol solution containing internal standard (LPA17:0) was added directly for protein precipitation, which was used as a system control sample. 2 μL of the series of concentration working solution was taken, and 198 μL of human blank plasma was added, and the concentration was 0-10 μM, and the sample was placed in a 37℃ incubator containing 5% CO2, and incubated for 2 hours. After incubation, 10 μL of the plasma sample was taken, and an appropriate volume of ice methanol solution containing internal standard (LPA17:0) was added for protein precipitation, and after centrifugation, the supernatant was taken, and LC / MS / MS was used for detection of LPA18:2, and software was used for analysis to calculate the IC 50 value of the compound, see Table 2.

[0843] Table 2. IC of the compound of the present application in human whole blood analysis 50

[0844] +: ≥1000 nM; ++: 500-1000 nM; +++: 100-500 nM; ++++: 0.01-100 nM

[0845]

[0846]

[0847] Note: ND: not tested

[0848] As can be seen from Table 2, the compound of the present application can also effectively inhibit ATX in human plasma, thereby inhibiting the hydrolysis of LPC into LPA, and the IC 50 value of most of the compounds is less than 100 nM.

[0849] In summary, the compound of the present application has good inhibitory activity on ATX, has excellent in vitro and in vivo pharmacodynamic and pharmacokinetic properties, and has a good clinical application prospect.

[0850] The technical features of the above-described embodiments can be combined in any manner. In order to make the description concise, all possible combinations of the technical features in the above-described embodiments are not described, however, as long as the combinations of the technical features do not exist contradictions, they should be considered as the scope of the present disclosure.

[0851] The above embodiments only express several implementation manners of the present application, and the description is more specific and detailed, but it should not be understood as a limitation on the scope of the patent. It should be noted that for ordinary skilled persons in the art, without departing from the concept of the present application, several modifications and improvements can be made, which are within the scope of protection of the present application. Therefore, the protection scope of the patent of the present application should be subject to the appended claims.

Claims

1. A compound, which is a compound of Formula (Ic), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture of the compound of Formula (Ic): (Ic), wherein, m is 0, 1; t is 1. ， 3. The compound of claim 1, wherein, the compound has a structure of any one of Formulas (Id)-(Ig): wherein, m1 is 1, 2; n1 is 0.

11. A compound, which is a compound having one of the following structures: or a pharmaceutically acceptable salt, stereoisomer, tautomer, or mixture thereof. Cy is , , , , , , , , , or ; wherein said Cy is optionally substituted with 1 or 2 R 4 ; Y is -(L 1 -W 1 ) m -L 2 -; L 1 is absent, or L 1 is -C(=0)-; W 1 for C 1-4 alkylene; L 2 is absent, or L 2 is -N(R b )-, -C(=O)N(R c )-, -N(R d )C(=O)N(R c )-, -S(=O) 0-2 -, -S(=O) 1-2 N(R e )-; Z is H, C 1-4 alkyl, C 3-8 cycloalkyl, C 2-7 heterocyclyl, wherein the C 1-4 alkyl, C 3-8 cycloalkyl, C 2-7 heterocyclyl is optionally substituted with one R 5 substituent; R 1a is C 1-4 alkyl; R 2 are each independently C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl; R 3 R is -CN; R 4 are each independently C 1-4 alkyl, C 1-4 hydroxyalkyl, -C(=O)OR 8a , -C(=O)NR 9a R 9 ; R 5 are each independently -CN, -OH, F, Cl, Br, I, -C(=0)OR 8a ; R 6 are independently from each other F, Cl, Br, I; Each R 8a R 9 H and C are independent of each other. 1-6 alkyl; R 9a are each independently H, C 1-6 alkyl; each R b , R c , R d , R e is independently H, C 1-4 alkyl, or R 16 -C(=O)-; R 16 is H; and, 12. A pharmaceutical composition comprising a compound of any one of claims 1-11, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient includes a diluent or a carrier.

2. The compound of claim 1, wherein, R 1a is methyl.

14. The pharmaceutical composition of claim 13, further comprising an additional therapeutic agent. each R is independently H or C1-C6alkyl; 8a , R is independently H or C1-C6alkyl; 9 each R is independently H or C1-C6alkyl; 1-4 alkyl; R 9a is H or C 1-4 alkyl.

4. The compound of claim 1, wherein, each R b , R c , R d , R e is independently H, C 1-4 alkyl.

5. The compound of claim 1, wherein, R 5 is -CN, -OH, F, -C(=0)OR 8a .

6. The compound of claim 1, wherein, Z is H, methyl, tert-butyl, or Z is , , , , , , .

7. The compound of claim 1, wherein, each R is independently 2 each R is independently 8. The compound of claim 1, wherein, R 4 is C 1-4 alkyl, C 1-4 hydroxyalkyl.

9. The compound of claim 1, wherein, R 6 is F.

10. The compound of claim 1, wherein, 15. Use of a compound of any one of claims 1-11, or a pharmaceutical composition of any one of claims 12-14, in the manufacture of a medicament for preventing or treating a disease having an increased expression of ATX in a mammal. (Id), (Ie), (If), or (Ig), The disease having an increased expression of ATX includes a cancer, a fibrotic disease, a metabolic disease, a myelodysplastic syndrome, a cardiovascular disease, an autoimmune disease, an inflammation, a nervous system disease, or a pain. X 3 is N; The disease having an increased expression of ATX is idiopathic pulmonary fibrosis or liver fibrosis. ​ ​ （1）， （2）， （3）， （4）， （5）， （6）， （8）， （9）， （10）， （11）， （12）， （14）， （16）， （17）， （19）， （20）， （21）， （22）， （23）， （26）， （27）， （31）， （33）， （84）， （108）， （109）， （110）， （111）， （113）， （114）， （115）， （116）， （117）， （118）， （119）， （120）， （121）， （122）， （123）， （124）， （125）， （126）， （127）， （128）， （129）， （130）， （131）， （132）， （133）， （134）， （142）， （143）， （144）， （145）， （146）， （147）， （149）， （150）， （151）， （152）， （153）， （154）， （155）， （156）， （157）， （158）， （162）， （163）， （165）， （169）， （172）， （174）， ​ ​ 13. The pharmaceutical composition of claim 12, wherein, ​ ​ ​ 16. Use according to claim 15, wherein, ​ 17. The use according to claim 16, wherein, ​

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