2-amino-3-carbonylimidazopyridine and pyrazolopyridine compounds

Abstract

The present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutical composition comprising the compound, and a method of using the compound for treating or preventing inflammatory and autoimmune diseases, especially neuroinflammatory diseases.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 078,372, filed September 15, 2020. The entire disclosure of the application identified in this paragraph is incorporated herein by reference. Technical Field

[0003] This disclosure generally relates to compounds having enzyme inhibitory activity, pharmaceutical compositions comprising the compounds, and methods of treating diseases using the compounds. Background Technology

[0004] Receptor-interacting protein kinases (RIPKs), belonging to the Ser / Thr and Tyr kinase family, play crucial roles in inflammation and innate immunity. The kinase activities of RIPK1 and RIPK3 have been found to be essential for the activation of necrotic cell death pathways by various stimuli, including the TNFα cytokine family, interferon (IFN), and Toll-like receptor (TLR) ligands (Christofferson and Yuan, 2010; Vanlangenakker et al., 2012). Importantly, RIPK1 / 3 kinases are associated with a variety of pathological settings for which effective therapies are currently lacking, including stroke, myocardial infarction, retinal injury, fatal systemic inflammatory response syndrome (SIRS), chronic intestinal and skin inflammation, and acute pancreatitis (Linkermann and Green, 2014).

[0005] RIPK2 is another RIP kinase involved in NF-κB activation, mitogen-activated protein kinase (MAPK), and apoptosis. RIPK2's kinase activity is dispensable for signal transduction via NF-κB and MAPK JNK ('Jun N-terminal kinase'), but essential for the activation of MAPK ERK2. RIPK2's most prominent function is mediating signal transduction from NOD1 and NOD2 ('nucleotide-binding oligomerization domain') proteins, which are cytosol pathogen recognition receptors that activate pro-inflammatory and antibacterial responses in response to bacterial peptidoglycan in macrophages. NOD1 and NOD2 are homologous proteins composed of a caspase recruitment domain (CARD), a nucleotide-binding domain, and a leucine-rich repetitive sequence. Upon recognition of its ligand, NOD1 or NOD2 recruits RIPK2 via CARD-CARD isotype interactions. This process promotes RIPK2 ubiquitination and activation of the TAK1 and IKK complex, thereby activating NF-κB and MAPK, as well as the production of pro-inflammatory cytokines by macrophages. RIPK2 also recruits various ubiquitin E3 ligases to the NOD2 complex, including XIAP (“X-chromosome-linked apoptosis inhibitor”), cIAP1 and cIAP2, PELL3, and LUBAC. XIAP deficiency has been shown to impair NOD1 or NOD2-mediated RIPK2 ubiquitination and inflammatory signaling. XIAP is recruited to the NOD2–RIPK2 complex by binding to the kinase domain of RIPK2, leading to K63 ubiquitination of RIPK2 and recruitment of LUBAC; this effectively activates NF-κB and MAPK, as well as the production of cytokines in macrophages. The ubiquitination sites of RIPK2 (Lys209, Lys410, and Lys538) play a crucial role in its function of signal transduction mediated by NOD1 and NOD2. The D146N kinase-inactivating mutant of RIPK2 retains the ability to bind XIAP and activate NOD2 signaling, indicating that RIPK2 kinase activity is not required for signaling via NOD1 and NOD2.

[0006] The NOD2-RIPK2 pathway has garnered particular interest due to its role in granulomatous inflammatory diseases, including inflammatory bowel disease (IBD). Such pathologies can be caused by positive or negative dysregulation of this pathway (Caruso et al., 2014; Josens et al., 2012; Philpott et al., 2014). Genetic variations in NOD2 are the strongest susceptibility factors for Crohn's disease (Hugot et al., 2001; Josens et al., 2012; Ogura et al., 2001a). Crohn's disease-associated mutations disrupt the binding of NOD2 to MDPs and may induce excessive inflammatory signaling from other pattern recognition receptors, including NOD1 (Couturier-Maillard et al., 2013; Inohara et al., 2003). In contrast, mutations in the second major Crohn's disease susceptibility factor, ATG16L1, disrupt the inhibitory interaction with NOD2, thereby increasing RIPK2 activation (Sorbara et al., 2003). RIPK2 overactivation has also been reported in pediatric Crohn's disease (Negroni et al., 2009). Furthermore, gain-of-function of the NOD2-RIPK2 pathway is associated with Blau syndrome, early-onset sarcoidosis, allergic airway inflammation, and multiple sclerosis (Goh et al., 2013; Jun et al., 2013; Shaw et al., 2011). Overall, these data establish RIPK2 as a key molecule for understanding the pathogenesis of IBD and as a potential therapeutic target for a wide range of inflammatory and autoimmune diseases, including neuroinflammatory diseases.

[0007] Alpha-synuclein is part of a large family of proteins, including β- and γ-synuclein, as well as synaptoproteins. Alpha-synuclein is expressed in a normal synaptic state and is thought to play a role in neuroplasticity, learning, and memory. Some studies have shown that alpha-synuclein plays an important role in the pathogenesis of Parkinson's disease. Molecular changes in alpha-synuclein that increase protein misfolding and aggregation have a direct role in disease pathogenesis. Alpha-synuclein aggregation contributes to the formation of Lewy bodies and neutral bodies, which are pathological markers of Parkinson's disease and alpha-synucleinopathy. Activation of the tyrosine kinase c-abl contributes to alpha-synuclein-induced neurodegeneration.

[0008] c-abl, a tightly regulated, non-receptor protein tyrosine kinase, is involved in a wide range of cellular processes, including growth, survival, and stress responses (Nat Rev Mol Cell Biol, 2004, 5:33-44). c-abl also regulates multiple cellular processes and participates in the development of the central nervous system by controlling neurogenesis. Recently, increasing evidence from various experimental model systems has also shown that c-abl is activated in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Niemann-Pick type C disease, and tau protein diseases (Human Molecular Genetics, 2014, Vol.23, No.11).

[0009] The stress signaling non-receptor tyrosine kinase c-abl links Parkinson's disease to its sporadic form via tyrosine phosphorylation. Tyrosine phosphorylation of parkin by c-abl is a major post-translational modification that leads to parkin dysfunction and disease progression in sporadic Parkinson's disease. Inhibition of c-abl offers a novel therapeutic opportunity to halt the progression of Parkinson's disease (The Journal of Neuroscience, 2011, 31(1):157-163). Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive death of motor neurons. Knockdown of c-abl with small interfering RNA (siRNA) can also rescue motor neuron degeneration in ALS (Imamura et al., Sci. Transl. Med. 9, 2017). Multiple system atrophy (MSA) is a rare, rapidly progressing neurodegenerative disease for which there is currently no treatment. In MSA, α-synuclein accumulates in neurons and oligodendrocytes of the substantia nigra, striatum, olive pons cerebellum and spinal cord (J Neural Transm Vienna Austria 1996.2016;123(6)).

[0010] In transgenic and lentiviral gene transfer models, administration of the tyrosine kinase inhibitor nilotinib reduced c-abl activity and improved autophagic clearance of α-synuclein. Activation of c-abl in the mouse forebrain induces neurodegeneration in the hippocampus and striatum. Therefore, increased c-abl activity via phosphorylation may be associated with α-synuclein pathology detected in Parkinson's disease and other neurodegenerative diseases (Hum Mol Genet. 2013 Aug 15). c-Abl is a potential therapeutic target for α-synucleinopathy, Parkinson's disease, Alzheimer's disease, ALS, Lewy body dementia, and MSA. Summary of the Invention

[0011] This disclosure provides a compound having RIPK2 and c-abl kinase inhibitory activity, a composition comprising the compound, and a method for treating inflammatory and / or autoimmune diseases, particularly neuroinflammatory diseases. In one embodiment, the compound is a compound of formula (I):

[0012]

[0013] In another embodiment, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of the compound described herein and a pharmaceutically acceptable carrier.

[0014] In another embodiment, this disclosure provides a method for inhibiting or treating neurodegenerative diseases, comprising administering a therapeutically effective amount of one or more of the compounds described herein to a subject in need of such treatment. Detailed Implementation

[0015] The following description is merely illustrative in nature and is not intended to limit this disclosure, its application, or its uses.

[0016] definition

[0017] For clarity, the general terms used in this disclosure are defined herein.

[0018] The terms “substituent”, “group”, “fraction”, and “segment” may be used interchangeably in this specification.

[0019] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group having at least one unsaturated site, i.e., a carbon-carbon, sp2 double bond. In one embodiment, the alkenyl group has 2 to 12 carbon atoms. In some embodiments, the alkenyl group is C2-C. 10 Alkenyl or C2-C6 alkenyl. Examples of alkenyl include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0020] As used herein, the term "alkoxy" is RO-, where R is an alkyl group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, and propoxy.

[0021] As used herein, the term "alkoxyalkyl" refers to an alkyl moiety substituted with an alkoxy group. Examples of alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, and ethoxyethyl.

[0022] As used herein, the term "alkoxycarbonyl" is ROC(O)-, where R is an alkyl group as defined herein. In various embodiments, R is C1-C2. 10Alkyl or C1-C6 alkyl.

[0023] As used herein, the term "alkyl" refers to a straight-chain or branched hydrocarbon group. In one embodiment, the alkyl group has 1 to 12 carbon atoms. In some embodiments, the alkyl group is C1-C2. 10 Alkyl or C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "Lower alkyl" refers to alkyl groups having 1 to 4 carbon atoms.

[0024] As used herein, when the term "C1-C6" is used, it indicates a number of carbon atoms from 1 to 6. For example, C1-C6 alkyl means an alkyl group with any integer number of carbon atoms from 1 to 6.

[0025] As used herein, the term "alkylamino" refers to an amino group substituted with one or more alkyl groups. "N-(alkyl)amino" is RNH-, and "N,N-(alkyl)2amino" is R2N-, wherein the R group is an alkyl group as defined herein and may be the same or different. In various embodiments, R is C1-C. 10 Alkyl or C1-C6 alkyl. Examples of alkylamino groups include methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, and methylethylamino.

[0026] As used herein, the term "alkylaminoalkyl" refers to an alkyl moiety substituted with an alkylamino group, wherein the alkylamino group is as defined herein. Examples of alkylaminoalkyl groups include methylaminomethyl and ethylaminomethyl.

[0027] As used herein, the term "alkynyl" refers to a straight-chain or branched carbon chain group having at least one unsaturated site, namely a carbon-carbon-sp triple bond. In one embodiment, the alkynyl group has 2 to 12 carbon atoms. In some embodiments, the alkynyl group is C2-C. 10 Alkynyl or C2-C6 alkynyl. Examples of alkynyl groups include alkynyl (-C≡CH) and propynyl (-CH2C≡CH).

[0028] As used herein, the term "aryl" refers to any monocyclic or bicyclic carbocyclic ring with up to seven atoms per ring, wherein at least one ring is aromatic, or an aromatic ring system with five to fourteen carbon atoms, comprising a carbocyclic aromatic group fused with a five- or six-membered alkyl group. Representative examples of aryl groups include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracel, fluorenyl, indene, azulel, and indanyl. The carbocyclic aromatic group may be unsubstituted or optionally substituted.

[0029] As used herein, the term "cycloalkyl" is a hydrocarbon group comprising at least one saturated or partially unsaturated ring structure and linked via a ring carbon. In various embodiments, it refers to a saturated or partially unsaturated C3-C... 12 Circular portion, saturated or partially unsaturated C3-C 12 Examples of cyclic moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. "Cycloalkoxy" is RO-, where R is a cycloalkyl group.

[0030] As used herein, the terms “halogen” and “halogenated” refer to chlorine (-Cl), bromine (-Br), fluorine (-F), or iodine (-I). “Haloalkoxy” refers to an alkoxy group substituted with one or more halogen groups, and examples of haloalkoxy groups include, but are not limited to, -OCF3, -OCHF2, and -OCH2F. “Haloalkoxyalkyl” refers to an alkyl moiety substituted with a haloalkoxy group, wherein the haloalkoxy group is as defined herein. Examples of haloalkoxyalkyl groups include trifluoromethoxymethyl, trifluoroethoxymethyl, and trifluoromethoxyethyl. “Haloalkyl” refers to an alkyl moiety substituted with one or more halogen groups. Examples of haloalkyl groups include -CF3 and -CHF2.

[0031] As used herein, the term "heteroalkyl" refers to a straight-chain or branched alkyl group having 2 to 14 carbons (2 to 10 carbons in some embodiments) in the chain, wherein one or more carbons are replaced by a heteroatom selected from S, O, P, and N. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, alkyl sulfides, etc.

[0032] As used herein, the term "heterocyclic group" includes heteroaryl groups as defined below, and refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic group having 2 to 14 ring carbon atoms, and having 1 to 4 heteroatoms selected from P, N, O, and S in addition to the ring carbon atoms. In various embodiments, the heterocyclic group is attached to another part via carbon or via a heteroatom, and is optionally substituted by carbon or a heteroatom. Examples of heterocyclic groups include azirrobutane, benzimidazolyl, benzofuranyl, benzofuranazonyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazoyl, carbaolinyl, cinnamolinyl, furanyl, imidazoyl, dihydroindolyl, indolyl, indolazinyl, indolazolyl, indolazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthiaridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxazoline, oxazoline, oxazoline, oxadiazolyl, pyranyl, pyrazinyl, pyridazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrroleyl, quinazolinyl, quinolinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazo[pyridinyl]pyridinyl, thiadiazolyl, thiazolyl Thiophene, triazolyl, aziridine, 1,4-dioxane, hexahydroaziridine, piperazinyl, piperidinyl, pyridin-2-yl, pyrrolyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophene, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyldihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrroleyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiazolyl, dihydrothiaphene, dihydrotriazolyl, dihydroaziridine, methylenedioxybenzoyl, tetrahydrofuranyl and tetrahydrothiaphene and their N-oxides. "Heterocyclic oxy group" is RO-, where R is a heterocyclic group. "Heterocyclic thio group" is RS-, where R is a heterocyclic group.

[0033] As used herein, the term "3- or 4-membered heterocyclic group" refers to a monocyclic ring having 3 or 4 ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S. Non-limiting examples of 3- or 4-membered heterocyclic groups include acridinel, 2H-acridinyl, oxetyl, thiaranyl, aziridine, 2,3-diacetyl, aziridine, 1,3-diazabolidine, oxetyl, 2H-oxetyl, thiohepyl, and 2H-thienyl.

[0034] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring having up to seven atoms in each ring, wherein at least one ring is aromatic and contains one to four heteroatoms selected from the following: non-limiting examples of heteroaryl include pyridinyl, thiopheneyl, furanyl, pyrimidinyl, imidazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrroleyl, pyridazinyl, quinolinyl, isoquinolinyl, benzofuranyl, dibenzofuranyl, dibenzothiopheneyl, benzothiopheneyl, indolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoydinolyl, benzotriazolyl, purinel, thianaphthyl, and pyrazinyl. The linkage of heteroaryl groups can occur via an aromatic ring, or, if the heteroaryl group is bicyclic or tricyclic and one of the rings is not aromatic or does not contain a heteroatom, it can be linked via a non-aromatic or heteroatom-free ring. "Heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group. "Heteroaryloxy group" is RO-, where R is a heteroaryl group.

[0035] As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with a hydroxyl group (-OH), wherein the alkoxy group is as defined herein. An example of a hydroxyalkoxy group is a hydroxyethoxy group.

[0036] As used herein, the term "hydroxyalkyl" refers to a straight-chain or branched chain with a monovalent C1-C6 valence that is substituted with at least one hydroxyl group. 10 Examples of hydrocarbon groups, specifically hydroxyalkyl groups, include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0037] As used herein, the term “pharmaceutical acceptable” means a pharmaceutical preparation that is generally considered safe for such use, has been formally approved for such use by a national or state regulatory agency, or is listed in the United States Pharmacopeia or other recognized pharmacopoeias for use in animals, especially humans.

[0038] As used herein, the term "pharmaceuticalally acceptable carrier" means a diluent, adjuvant, excipient, or carrier, or other pharmaceutically acceptable components administered together with the compounds of the present invention.

[0039] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that enhances a desired pharmacological activity. Examples of pharmaceutically acceptable salts include acid addition salts, metal salts, and amine salts formed with inorganic or organic acids. Examples of acid addition salts formed with inorganic acids include salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxy-benzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2,2,2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis(3-hydroxy-2-naphthoic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. Examples of metal salts include those formed with sodium, potassium, calcium, magnesium, aluminum, iron, and zinc ions. Examples of amine salts include those formed with ammonia and organic nitrogenous bases, which are strong enough to form salts with carboxylic acids.

[0040] As used herein, the term "substituted" refers to any of the above-described groups (i.e., alkyl, aryl, heteroaryl, heterocyclic, or cycloalkyl) wherein at least one hydrogen atom of the substituted portion is substituted by a substituent. In one embodiment, each carbon atom of the substituted group is substituted by no more than two substituents. In another embodiment, each carbon atom of the substituted group is substituted by no more than one substituent. In the case of ketone substituents, both hydrogen atoms are substituted by oxygen, which is attached to the carbon atom via a double bond. Unless otherwise specified, substituents include halogen, hydroxyl, (lower) alkyl, haloalkyl, monoalkyl or dialkylamino, aryl, heterocyclic, -NO2, B(OH)2, BPi, -NR. a R b -NR a C(=O)R b -NR a C(=O)NR a R b -NR a C(=O)OR b -NR a SO2R b -OR a -CN, -C(=O)R a -C(=O)ORa, -C(=O)NR a R b -OC(=O)R a -OC(=O)OR a-OC(=O)NR a R b -NR a SO2R b -PO3R a -PO(OR) a (OR) b -SO2R a -S(O)R a -SO(N)R a (e.g., sulfoxide imine), -(R a S = NR b (e.g., alkylthioimine) and -SRa, where R a and R b The same or different and independently hydrogen, halo, amino, alkyl, haloalkyl, aryl or heterocyclic, or wherein R a and R b Together with the nitrogen atoms they are attached to, they form heterocycles. R a and R b It can be a complex form based on the atoms they are connected to.

[0041] As used herein, the term "therapeuticly effective amount" refers to, when applied to the compounds of the present invention, an amount sufficient to improve, alleviate, stabilize, reverse, slow, or delay disease progression or symptoms. In one embodiment, the method of the present invention provides administration of a combination of compounds. In this case, the "therapeuticly effective amount" is the amount of the compounds of the present invention in the combination sufficient to cause the desired biological effect.

[0042] As used herein, the terms “treatment” or “under treatment” refer to improving or reversing the progression or severity of a disease or condition, or improving or reversing one or more symptoms or side effects of such a disease or condition. As used herein, “treatment” or “under treatment” also refers to inhibiting or blocking, such as delaying, preventing, suppressing, or hindering the progression of a system, condition, or state of a disease or condition. For the purposes of this invention, “treatment” or “under treatment” also refers to a method of obtaining a beneficial or desired clinical outcome, wherein “beneficial or desired clinical outcome” includes, but is not limited to, the reduction of symptoms, the reduction of the severity of a condition or disease, the stabilization (i.e., non-deterioration) of a disease or condition, the delay or mitigation of a disease or condition, the improvement or alleviation of a disease or condition, and partial or complete remission of a disease or condition.

[0043] In another embodiment, the compound shown in formula (I) is used to modulate the activity of the RIPK2 protein.

[0044] As used herein, the term "regulation" refers to altering the catalytic activity of a protein kinase. Regulation specifically refers to activating or inhibiting the catalytic activity of a protein kinase, depending on the concentration of compounds or salts the protein kinase is exposed to, or more preferably, regulation refers to inhibiting the catalytic activity of a protein kinase. The term "catalytic activity," as used herein, refers to the phosphorylation rate of tyrosine, serine, or threonine under the direct or indirect influence of a protein kinase.

[0045] Pharmacological inhibitors of kinase activity are mainly divided into three categories: (1) Type I or “DFG-in” ATP competitive inhibitors, which directly compete with ATP binding sites (i.e., dual SRrc ABL inhibitors, dasatinib); (2) Type II or “DFG-out” ATP competitive inhibitors, which, in addition to binding to ATP binding sites, also bind to adjacent hydrophobic binding sites that are only accessible when the kinase is in an inactive conformation (i.e., the activation loop is oriented in a conformation that prevents substrate binding) (i.e., imatinib, nilotinib); and (3) non-ATP competitive inhibitors, which bind to sites other than the ATP binding sites that affect kinase activity (i.e., GNF-2).

[0046] As used herein, the phrase “one or more of this / the disclosed compounds” includes any compound represented by formula (I), as well as its inclusion compounds, hydrates, solvates, or polymorphs. Furthermore, even if the term “one or more of the compounds of this disclosure” does not refer to its pharmaceutically acceptable salt, the term includes its salt. In one embodiment, the compounds of this disclosure include stereochemically pure compounds, such as those substantially free of (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, greater than 97% ee, or greater than 99% ee) other stereoisomers. That is, if a compound or its salt represented according to formula (I) of this disclosure is a tautomer and / or stereoisomer (e.g., geometric isomers and conformational isomers), such isolated isomers and mixtures thereof are also included within the scope of this disclosure. If a compound or its salt has an asymmetric carbon in its structure, its active optical isomers and racemic mixtures thereof are also included within the scope of this disclosure.

[0047] As used herein, the term "polymorph" refers to the solid crystalline form of the compounds or complexes thereof disclosed herein. Different polymorphs of the same compound can exhibit different physical, chemical, and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., stability to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution (affecting bioavailability). Differences in stability may be caused by changes in chemical reactivity (e.g., different oxidation, causing a dosage form to discolor more rapidly when composed of one polymorph than when composed of another) or mechanical properties (e.g., tablets breaking apart during storage as a kinetically favorable polymorph transforms into a thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more prone to decomposition at high humidity). Different physical properties of polymorphs can affect their processing. For example, due to, for example, the shape or size distribution of their particles, one polymorph may be more likely to form solvates or may be more difficult to filter or wash away impurities than another.

[0048] As used herein, the term "solvent" refers to a compound or salt thereof according to this disclosure, which also includes stoichiometric or non-stoichiometric solvents bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and / or acceptable for human administration in small doses.

[0049] As used herein, the term "hydrate" means a compound or salt thereof according to the present disclosure, which also includes stoichiometric or nonstoichiometric water bound by noncovalent intermolecular forces.

[0050] As used herein, the term “inclusion compound” refers to a compound or its salt in lattice form that contains spaces (e.g., channels) in which guest molecules (e.g., solvents or water) are trapped.

[0051] The compounds disclosed herein

[0052] This disclosure provides compounds of formula (I):

[0053]

[0054] Or its pharmaceutically acceptable salt, wherein:

[0055] R 1 and R 2 Independently, it is -H, C1-C6 alkyl, C3-C6 carbocyclic, C1-C4 alkylyl (i.e., -(CO)C1-C4 alkyl), -(CO)C3-C6 carbocyclic, aryl, or heteroaryl, wherein each carbon is optionally substituted by one or more groups selected from halogens, alkyl, hydroxyalkyl, haloalkyl, and monoalkylaminoalkyl; or R 1 and R 2Together they form a 5-membered heterocyclic ring;

[0056] R 3 -H, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -O-cycloalkyl, -O-heterocyclic, -O-aryl, -O-heteroaryl, -NR c -alkyl, -NR c -cycloalkyl, -NR c -heterocyclic group, -NR c -Aryl, -NR c -heteroaryl, -NR c -NR c C(=O)R c Or -CF3, wherein each carbon is optionally replaced by one or more groups selected from halogens, alkyl, hydroxyalkyl, haloalkyl and monoalkylaminoalkyl;

[0057] R 4 and R 5 Independently -H, -OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, aryl, heteroaryl, heterocyclic or heteroalkyl, amino, -SCH3 or -CN;

[0058] R 6 Selected from -H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 carbocyclic, heterocyclic, aryl, heteroaryl, -NR c -Aryl, -NR c -heteroaryl, -O-aryl, -O-heteroaryl, where R 6 Optionally substituted by one or more groups, which are selected from halogen, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, trimethylsilylethoxymethyl, morpholinyl, piperazine, methylpiperazine, alkoxyalkenyl, -NO2, -NR a R b -NR a C(=O)R b -NR a C(=O)NR a R b -NR a C(=O)OR b -OR a -SR a -CN, -C(=O)R a -C(=O)OR a -C(=O)NR a R b -OC(=O)R a -OC(=O)OR a , and -OC(=O)NRa R b ;

[0059] R a and R b Independently -H, halogen, amino, alkyl, or haloalkyl;

[0060] R c It is -H, C1-C3 alkyl or cyclopropyl; and

[0061] X and Y are independently carbon or nitrogen, where X is N when Y is C, or X is C when Y is N.

[0062] In some implementation schemes, R 3 Selected from -H, methyl, isopropyl, butyl, methoxy, pyridyl, phenyl, cyclopropyl, cyclobutyl, pyrazolyl, aziridine, pyrimidinyl, pyrrolidinyl, cyclopropylamino, and indazole, wherein R 3 The substituent may be optionally replaced by one or more groups selected from halogens, alkyl groups, hydroxyalkyl groups, haloalkyl groups, and monoalkylaminoalkyl groups. Non-limiting representative compounds having such substituents can be found in Table 1.

[0063] In some implementation schemes, R 6 Selected from bromine, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, azaindolyl, indolyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, thiophenyl, furanyl, oxazolyl, thiazolyl, oxadiazolyl, thiazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazoleolopyridinyl, imidazoleolopyrimidinyl, imidazoleolopyrazinyl, pyrroletriazinyl, pyrazolopyridinyl, imidazoletriazinyl, purinyl, indazoleyl, benzofuranyl, benzothiophene, benzoxazolinyl, benzothiazolinyl, benzothiazolinyl, benzoimidazolinyl, oxindolyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinazolinyl, azaquinazolinyl, quinoxolinyl, azaquinoxolinyl, naphthyl, wherein R 6 Optionally substituted with one or more groups, which are selected from halogens, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, aminoalkyl groups, alkylamino groups, trimethylsilylethoxymethyl groups, morpholinyl groups, piperazine groups, methylpiperazine groups, and alkoxyalkenyl groups. Non-limiting representative compounds having such substituents can be found in Table 1.

[0064] In one embodiment, the compound represented by formula (I) is selected from the compounds represented by formula (II) and their pharmaceutically acceptable salts:

[0065]

[0066] Where R 3 R4 R 5 and R 6 The definition is as above.

[0067] In some implementation schemes, R 3 It is fluorocyclopropyl and R 6 The indolyl group is optionally substituted with one or more groups selected from halogens, hydroxyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, aminoalkyl groups, and tert-butoxycarbonyl groups. Non-limiting representative compounds having such substituents can be found in Table 1.

[0068] In some implementation schemes, R 3 It is fluorocyclopropyl, and R 6 Selected from bromine, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, azaindolyl, indolyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, thiophenyl, furanyl, oxazolyl, thiazolyl, oxadiazolyl, thiazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazoleolopyridinyl, imidazoleolopyrimidinyl, imidazoleolopyrazinyl, pyrrolotriazinyl, pyrazolopyridinyl, imidazoleolotriazinyl, purine, indazoleyl, benzofuranyl, benzothiophene, benzoxazolinyl, benzothiazolinyl, benzothiazolinyl, benzoimidazolyl, oxoindololinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinazolinyl, azaquinazolinyl, quinoxolinyl, azaquinoxolinyl, quinoxolinyl, azaquinoxolinyl, naphthyl, wherein R 6 Optionally substituted with one or more groups, which are selected from halogens, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, aminoalkyl groups, alkylamino groups, trimethylsilylethoxymethyl groups, morpholinyl groups, piperazine groups, methylpiperazine groups, and alkoxyalkenyl groups. Non-limiting representative compounds having such substituents can be found in Table 1.

[0069] In some implementation schemes, R 3 It is cyclopropyl and R 6 Selected from bromine, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, azaindolyl, indolyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, thiophenyl, furanyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazoleolopyridinyl, imidazoleolopyrimidinyl, imidazoleolopyrazinyl, pyrrolotriazinyl, pyrazolopyridinyl, imidazoleolotriazinyl, purine, indazoleyl, benzofuranyl, benzothiophene, benzoxazolinyl, benzothiazolinyl, benzothiazolinyl, benzoimidazolyl, oxoindololinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinazolinyl, azaquinazolinyl, quinoxolinyl, azaquinoxolinyl, quinoxolinyl, azaquinoxolinyl, naphthyl, where R 6Optionally substituted with one or more groups, which are selected from halogens, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, haloalkoxy groups, hydroxyalkyl groups, aminoalkyl groups, alkylamino groups, trimethylsilylethoxymethyl groups, morpholinyl groups, piperazine groups, methylpiperazine groups, and alkoxyalkenyl groups. Non-limiting representative compounds having such substituents can be found in Table 1.

[0070] In some implementation schemes, R 3 Selected from methyl, isopropyl, butyl, methoxy, pyridyl, phenyl, cyclobutyl, pyrazolyl, aziridine, pyrimidinyl, pyrrolidinyl, cyclopropylamino, and indazole, wherein R 3 The substituent may be optionally replaced by one or more groups selected from halogens, alkyl, hydroxyalkyl, haloalkyl, and monoalkylaminoalkyl. Non-limiting representative compounds with such substituents can be found in Table 1.

[0071] In another embodiment, the compound represented by formula (I) is selected from the compounds represented by formula (III) and their pharmaceutically acceptable salts:

[0072]

[0073] Where R 3 R 4 R 5 R6 is defined as above. Non-limiting representative compounds with such substituents can be found in Table 1.

[0074] In some embodiments, the compound represented by Formula I has R 1 and R 2 They are independently -H, alkyl, acetyl, tert-butoxycarbonyl, aminoethyl, dimethylaminoethyl, or methylaminoethyl; or R 1 and R 2 Together, they form a 5-membered heterocyclic group. Non-limiting representative compounds with this type of substituent can be found in Table 1, where R... 3 To R 6 As defined in equation (I) above.

[0075] This disclosure provides pharmaceutically acceptable salts of the above-described compounds. Pharmaceutically acceptable salts are defined as in the definition section. In some embodiments, the salt is a hydrochloride, tartrate, phosphate, or maleate.

[0076] Medical uses and treatments using compounds according to this disclosure

[0077] This disclosure also provides a method of treating a subject suffering from or susceptible to such a neurodegenerative disease or condition by administering to the subject a therapeutically effective amount of one or more of the compounds described above. In one embodiment, the treatment is preventative. In another embodiment, the treatment is palliative. In yet another embodiment, the treatment is restorative.

[0078] 1. Disease or symptom

[0079] The compounds of this disclosure, which inhibit RIPK2 and c-abl activity, can be used to treat or prevent neurodegenerative diseases or conditions. These compounds can be used to inhibit or block RIPK2 and c-abl kinase activity for the treatment of neurodegenerative diseases or conditions, or for the prevention of the worsening of such diseases. Therefore, this disclosure provides a method for inhibiting or blocking RIPK2 and c-abl activity in cells, wherein the cells are contacted with an effective amount of the compounds of this disclosure. In one embodiment, such cells are present in a subject (e.g., an Alzheimer's disease patient). In another embodiment, medical use is provided for treating or preventing inflammatory and / or autoimmune diseases, particularly neuroinflammatory diseases or conditions, in a subject using compounds according to this disclosure. The method of this disclosure includes administering a pharmaceutical composition containing a therapeutically or preventively effective amount of an inhibitor of RIPK2 and c-abl to a subject requiring treatment or prevention. Inflammatory and autoimmune diseases, particularly neuroinflammatory diseases or conditions, include, but are not limited to, alpha-synucleinopathy, Parkinson's disease, Lewy body dementia, multiple system atrophy (MSA), Alzheimer's disease, or amyotrophic lateral sclerosis (ALS).

[0080] 2 subjects

[0081] Suitable subjects for treatment according to this disclosure include mammalian subjects. Mammals according to this disclosure include, but are not limited to, humans, canines, felines, bovines, caprines, equines, sheep, suidae, rodents, rabbits, primates, etc., and include uterine mammals. Subjects can be of any sex and at any developmental stage. In one embodiment, the suitable subject for treatment according to this disclosure is a human.

[0082] 3. Administration and Dosage

[0083] The compounds of this disclosure are typically administered in therapeutically effective amounts. The compounds of this disclosure may be administered via any suitable route in the form of a pharmaceutical composition suitable for such route and at a dose effective for the intended treatment. Effective doses are typically taken as a single dose or split dose of about 0.001 to about 100 mg / kg body weight / day, preferably about 0.01 to about 50 mg / kg body weight / day. Depending on age, species, and the disease or condition being treated, dose levels below the lower limit of this range may be appropriate. In other cases, larger doses may be used without adverse side effects. Larger doses may also be divided into several smaller doses for administration throughout the day. Methods for determining appropriate doses are known in the art to which this disclosure pertains. For example, Remington: The Science and Practice of Pharmaceuticals, Mack Publishing Co., 20th edition, 2000.

[0084] Drug composition, dosage form and route of administration

[0085] To treat the aforementioned diseases or conditions, the compounds described herein or their pharmaceutically acceptable salts may be administered as follows:

[0086] Oral administration

[0087] The compounds disclosed herein can be administered orally, including by swallowing, so that the compounds enter the gastrointestinal tract, or be absorbed directly from the mouth into the bloodstream (e.g., oral or sublingual administration).

[0088] Suitable compositions for oral administration include solid, liquid, gel, or powder formulations, and have dosage forms such as tablets, lozenges, capsules, granules, or powders.

[0089] The oral administration composition can be formulated for immediate release or sustained release, including delayed or continuous release, and optionally has an enteric coating.

[0090] Liquid formulations may include solutions, syrups, and suspensions, and may be used in soft capsules or hard capsules. Such formulations may include pharmaceutically acceptable carriers such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulation may also include one or more emulsifiers and / or suspending agents.

[0091] In tablet dosage forms, the amount of drug present can be from about 0.05% to about 95% of the dosage form weight, more typically from about 2% to about 50%. In addition, tablets may contain a disintegrant, comprising from about 0.5% to about 35% of the dosage form weight, more typically from about 2% to about 25%. Examples of disintegrants include, but are not limited to, lactose, starch, sodium glycolate starch, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

[0092] The content of a suitable lubricant for tablets may be from about 0.1% to about 5% by weight, including but not limited to talc, silica, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, etc.

[0093] Suitable binders for tablets include, but are not limited to, gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Suitable diluents for tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose, and starch.

[0094] The amount of a suitable solubilizer for tablets may be from about 0.1% to about 3% by weight, and includes, but is not limited to, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol (natural or hydrogenated) castor oil, HCOR TM (Nikkol), oleate, Gelucire TM Caprylic / caprylic mono / diglycerides, sorbitan fatty acid esters, and Solutol HS TM .

[0095] Parenteral administration

[0096] The compounds disclosed herein can be directly administered into the bloodstream, muscles, or internal organs. Suitable routes of parenteral administration include intravenous, intramuscular, subcutaneous-intra-arterial, intraperitoneal, intrathecal, and intracranial administration. Suitable devices for parenteral administration include syringes (including needle-tipped and needleless syringes) and infusion methods.

[0097] Compositions for parenteral administration can be formulated for immediate or sustained release, including delayed or continuous release. Most parenteral formulations are aqueous solutions containing excipients, including salts, buffers, and isotonic agents. Parenteral formulations can also be prepared in dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These formulations can be used with suitable media, such as sterile water. Solubilizers can also be used to prepare parenteral solutions.

[0098] transdermal drug delivery

[0099] The compounds disclosed herein can be applied topically to the skin or transdermally. Formulations for this topical administration may include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, etc. Pharmaceutically acceptable carriers for topical administration formulations may include water, alcohol, mineral oil, glycerin, polyethylene glycol, etc. Topical or transdermal administration may also be performed via electroporation, iontophoresis, ultrasound transdermal therapy, etc.

[0100] Compositions for topical administration can be formulated to release immediately or sustainably, including delayed or sustained release.

[0101] combination therapy

[0102] The pharmaceutical compositions according to this disclosure may contain one or more additional therapeutic agents, for example, to enhance efficacy or reduce side effects. Therefore, in some embodiments, the pharmaceutical composition further contains one or more other therapeutic agents selected from the active ingredient, which can be used to treat or inhibit diseases directly or indirectly mediated by RIPK and c-abl kinases. Examples of such active ingredients are, but are not limited to, medicines for treating inflammatory and autoimmune diseases or conditions.

[0103] References for the preparation of pharmaceutical compositions

[0104] Methods for preparing pharmaceutical compositions for treating or preventing diseases or conditions are well known in the art to which this disclosure pertains. For example, pharmaceutically acceptable excipients, carriers, additives, etc., can be selected according to the Handbook of Pharmaceutical Excipients (7th edition), Remington: The Science and Practice of Pharmaceuticals (20th edition), the Encyclopedia of Pharmaceutical Technology (3rd edition), or Sustained-Release and Controlled-Release Drug Delivery Systems (1978), and then mixed with the compounds of this disclosure to prepare the pharmaceutical composition.

[0105] This disclosure provides a compound having multiple pharmacological effects by inhibiting RIPK2 and c-abl activity, a pharmaceutical composition using the compound as an effective drug, and the medical use of the compound, particularly for the treatment of neurodegenerative diseases or conditions, and a method of treatment or prevention comprising administering the compound to a subject requiring such treatment or prevention. The compounds of this disclosure and their pharmaceutically acceptable salts exhibit good safety and high selectivity for RIPK2 and c-abl, thus demonstrating excellent pharmaceutical properties.

[0106] Example

[0107] The present disclosure is described in considerable detail below by way of example to aid those skilled in the art in understanding it. However, the following embodiments are provided by way of illustration and are not intended to limit the scope of the invention. It will be apparent that various changes may be made without departing from the spirit and scope of the invention or without sacrificing all its material advantages.

[0108] Synthesis of the compound shown in formula (I)

[0109] The synthetic methods from A to S are used to prepare the following compounds. Illustrative synthetic examples of some compounds of this disclosure are described below, and other compounds can be prepared using different starting or reactant materials through methods similar to those described below.

[0110] Synthesis Method A

[0111] Example 1 (2-amino-6-bromoimidazolo[1,2-a]pyridin-3-yl)(cyclopropyl) methyl ketone

[0112]

[0113] To a DMF (50 mL) solution of cyclopropanecarboxylic acid (3.17 g, 36.78 mmol, 2.91 mL, 1.3 equivalences), EDCI (6.51 g, 33.95 mmol, 1.2 equivalences), HOBt (4.59 g, 33.95 mmol, 1.2 equivalences), and TEA (8.59 g, 84.89 mmol, 11.82 mL, 3 equivalences) were added. The mixture was stirred at 15 °C for 1 hour, and then 6-bromoimidazolo[1,2-a]pyridine-2-amine (6 g, 28.30 mmol, 1 equivalence) was added. The final mixture was stirred at 15 °C for 18 hours. The mixture was poured into water (200 mL), extracted with ethyl acetate (300 mL x 3), washed with brine (500 mL x 2), dried over anhydrous sodium sulfate (Na₂SO₄), filtered, and concentrated under vacuum. The residue was purified by grinding with ethyl acetate (50 mL), filtered, and the filter cake was concentrated. Example 1 (2.4 g, 8.25 mmol, yield 30.28%, purity 96.3%) was given as a yellow solid.

[0114] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.70 (d, J = 1.2Hz, 1H), 7.60 (dd, J = 2.1, 9.3Hz, 1H), 7.32 (d, J = 9.3Hz, 1H), 6.62 (s, 2H), 2.46–2.37 (m, 1H), 1.02–0.90 (m, 4H); LCMS (electrospray) m / z 282.10 (M+2H)+.

[0115] Synthesis Method B

[0116] Example 6 1-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)ethane-1-one

[0117]

[0118] Step 1) 1-(2-amino-6-bromoimidazolo[1,2-a]pyridin-3-yl)ethane-1-one

[0119] To a solution of 6-bromoimidazolo[1,2-a]pyridine-2-amine (260 mg, 1.23 mmol, 1 equivalent) in DCM (20 mL), EDCI (358 mg, 1.84 mmol, 1.5 equivalent), HOBt (249 mg, 1.84 mmol, 1.5 equivalent), and TEA (186 mg, 1.84 mmol, 256 μL, 1.5 equivalent) were added. The mixture was stirred at 25 °C for 1 h, and then acetic acid (81 mg, 1.35 mmol, 1.1 equivalent) was added. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove the DCM solution, giving the residue. The crude product was purified by silica gel chromatography (the product was given in hexane / ethyl acetate = 1 / 2) to give compound 1 as a white solid (177 mg, 0.67 mmol, yield 57%).

[0120] 1 H NMR (400MHz, DMSO-d6) δ9.66 (s, 1H), 7.61 (dd, J = 9.3, 2.2Hz, 1H), 7.33 (d, J = 9.3Hz, 1H), 6.51 (s, 2H), 2.43 (s, 3H).

[0121] Step 2) 1-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)ethane-1-one

[0122] To a solution of compound 1 (150 mg, 0.590 mmol, 1 equivalent) in dioxane (6 mL) and H₂O (2 mL), (3-fluoro-2-methylphenyl)boronic acid (136 mg, 0.883 mmol, 1.5 equivalent), Na₂CO₃ (125 mg, 1.179 mmol, 2.0 equivalent), and Pd(dppf)Cl₂ (43 mg, 0.06 mmol, 0.1 equivalent) were added. The mixture was heated at 120 °C for 30 min under microwave, cooled to room temperature, filtered through a diatomaceous earth mat to remove the solid, and separated between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, separated, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 1 / 1) to give Example 6 (122 mg, 0.430 mmol, 73% yield) an ivory-like solid.

[0123] 1H NMR (400MHz, DMSO-d6) δ 9.49 (s, 1H), 7.51 (dd, J = 9.2, 1.8Hz, 1H), 7.41 (d, J = 8.2Hz, 1H), 7.38–7.29 (m, 1H), 7.23 (t, J = 8.5Hz, 1H), 7.16 (d, J = 7.1Hz, 1H), 6.47 (s, 2H), 2.44 (s, 3H), 2.16 (d, J = 2.2Hz, 3H); LCMS (electrospray) m / z 284.10 (M+H)+.

[0124] Synthesis method C

[0125] Example 24 (2-((2-(dimethylamino)ethyl)amino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2- [a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methyl ketone

[0126]

[0127] To a DMF (1.5 mL) solution of Example 5 (100 mg, 0.30 mmol, 1 equivalent), 2-bromo-N,N-dimethylethane-1-amine HBr (105 mg, 0.45 mmol, 1.5 equivalent), K₂CO₃ (124 mg, 0.90 mmol, 3 equivalent), and TBAB (9.6 mg, 0.03 mmol, 0.1 equivalent) were added. The reaction mixture was heated to 100 °C in a microwave oven for 30 minutes. The reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0–20% MeOH gradient in DCM) to give Example 24 (10 mg, 8.3% yield).

[0128] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.77 (s, 1H), 8.22–8.09 (m, 2H), 7.44–7.40 (m, 1H), 7.35–7.28 (m, 1H), 7.24–7.12 (m, 1H), 5.37–5.16 (m, 1H), 4.54 (s, 2H), 4.09 (d, J = 4.9 Hz, 2H), 3.17 (d, J = 3.8 Hz, 6H), 2.83–2.66 (m, 4H), 2.33–2.08 (m, 3H), 1.96 (dtd, J = 23.5, 6.8, 3.2 Hz, 1H), 1.33–1.23 (m, 1H); LCMS (electrospray) m / z 399.2 (M+H)+.

[0129] Synthesis method D

[0130] Example 28 (2-amino-6-(5-methylthiazolyl-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2- Fluorocyclopropyl methyl ketone.

[0131]

[0132] Step 1) 2,2,2-trifluoro-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)imidazo[1,2-a]pyridin-2-yl)acetamide

[0133] At room temperature, a solution of N-(6-bromoimidazolo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide (1.0 g, 3.24 mmol, 1 equivalent) in DMSO (30 mL) was added with bis(pinacolato)diboron (1.0 g, 4.21 mmol, 1.3 equivalent), Pd(dppf)Cl2 (234 mg, 0.32 mmol, 0.1 equivalent), and KOAc (953 mg, 9.72 mmol, 3 equivalent). The mixture was then heated at 90 °C for 7 hours, cooled to room temperature, filtered through a diatomaceous earth mat to remove solids, and separated between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, separated, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 1 / 2) to give compound 2 as a beige solid (602 mg, 1.69 mmol, yield 52.4%).

[0134] Step 2) 6-(5-methylthiazolyl-4-yl)imidazo[1,2-a]pyridine-2-amine

[0135] Compound 2 (598.35 mg, 1.68 mmol, 1.5 equivalence), Na2CO3 (238.11 mg, 2.25 mmol, 2 equivalence), and Pd(dppf)Cl2 (82.19 mg, 112.33 μmol, 0.1 equivalence) were added to a solution of 4-bromo-5-methylthiazole (200 mg, 1.12 mmol, 1 equivalence) in dioxane (4 mL) and H2O (1 mL). The mixture was then stirred at 90 °C under N2 for 16 h. The reaction mixture was concentrated under reduced pressure to remove H2O and the dioxane solution, yielding a residue. The residue was purified by reversed-phase rapid chromatography (MeCN / H2O, 0.05% TFA, 25%–30%) to give the product. Compound 3 (80 mg, 347.39 μmol, yield 30.93%) was given as a yellow solid.

[0136] Step 3)(2-amino-6-(5-methylthiazolyl-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone

[0137] To a DCM (2 mL) solution of (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (31.64 mg, 303.97 μmol, 1 equivalent), EDCI (69.93 mg, 364.76 μmol, 1.2 equivalent), HOBt (49.29 mg, 364.75 μmol, 1.2 equivalent), and TEA (92.27 mg, 911.90 μmol, 126.92 μL, 3 equivalent) were added. The mixture was stirred at 25 °C for 1 h, and then compound 3 (70 mg, 303.97 μmol, 1 equivalent) was added. The mixture was stirred at 25 °C for 11 h. The reaction mixture was concentrated under reduced pressure to remove the DCM solution, giving the residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 15%-45%, 10 min). Example 28 (53 mg, 167.53 μmol, yield 55.12%) was given as a white solid.

[0138] 1 H NMR (400MHz, DMSO-d6) δ 10.01-9.88 (m, 1H), 8.99 (br d, J = 0.9Hz, 1H), 7.91-7.84 (m, 1H), 7.44 (br d, J = 9.0Hz, 1H), 6.68 (br s, 2H), 5.29-5.07 (m, 1H), 2.68-2.58 (m, 5H), 1.93-1.84 (m, 1H), 1.20-1.08 (m, 1H); LCMS (electrospray) m / z 317.20 (M+H)+.

[0139] Synthesis method E

[0140] Example 33 N-(3-acetyl-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)acetamide And Example 37 N-acetyl-N-(3-acetyl-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)ethyl amide

[0141]

[0142] To the DCM (10 mL) solution of Example 6 (250 mg, 0.88 mmol, 1 equivalent), T3P 50% solution (842 mg, 1.32 mmol, 1.5 equivalent) and TEA (295 mg, 2.91 mmol, 406 μL, 3.3 equivalent) were added, and the mixture was stirred at 0 °C for 1 hour. Then, acetic acid (132 mg, 2.21 mmol, 2.5 equivalent) was added. The mixture was stirred at 25 °C for 15 hours. The reaction mixture was concentrated under reduced pressure to remove the DCM solution, giving a residue. The crude product was purified by silica gel chromatography (hexane / ethyl acetate = 1 / 2) to give the white solids of Example 33 (24.9 mg, 0.077 mmol, yield 8.7%) and Example 37 (81.7 mg, 0.222 mmol, yield 25.3%).

[0143] Example 33: 1 H NMR (400MHz, DMSO-d6) δ 10.51 (s, 1H), 9.51 (s, 1H), 7.81 (d, J = 9.3Hz, 1H), 7.68 (dd, J = 9.1, 1.9Hz, 1H), 7.37 (dd, J = 14.0, 8.0Hz, 1H), 7.28 (t, J = 8.5Hz, 1H), 7.20 (d, J = 7.7Hz, 1H), 2.44 (s, 3H), 2.22-2.12 (m, 6H); LCMS (electrospray) m / z 326.10 (M+H)+:.

[0144] Example 37: 1 H NMR (400MHz, DMSO-d6) δ1H NMR (400MHz, DMSO-d6) δ9.57 (d, J=1.1Hz, 1H), 7.99-7.91 (m, 1H), 7.80 (dd, J=9.1, 1.9Hz, 1H), 7.44-7.35 (m, 1H), 7.34-7.26 (m, 1H), 7.23 (d, J=7.7Hz, 1H), 2.37 (s, 3H), 2.35 (s, 6H), 2.20 (d, J=2.7Hz, 3H); LCMS (electrospray) m / z 368.10 (M+H)+.

[0145] Synthesis method F

[0146] Example 54 (6-(3-fluoro-2-methylphenyl)-2-(methylamino)imidazo[1,2-a]pyridin-3-yl)((1S, 2S)-2-fluorocyclopropyl)methyl ketone

[0147]

[0148] Example 5 Example 54

[0149] At -78°C, a 2M LDA solution of THF (113 μl, 0.225 mmol, 1.5 equivalence) was added dropwise to a THF solution of Example 5 (50 mg, 0.15 mmol, 1 equivalence). After 30 minutes, MeI (20 μl, 0.3 mmol, 2 equivalence) was added. The reaction mixture was stirred at -78°C for 2 hours. The mixture was then diluted with 10 mL of water and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0 to 10% gradient MeOH in DCM) to give Example 54 (3 mg, yield 5.8%).

[0150] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.56 (s, 1H), 7.59–7.53 (m, 3H), 7.35 (dd, J = 13.7, 8.2Hz, 1H), 7.27–7.18 (m, 3H), 5.28–5.08 (m, 1H), 4.80 (s, 1H), 3.07 (d, J = 4.4Hz, 3H), 2.31 (d, J = 18.7Hz, 1H), 2.18 (d, J = 2.2Hz, 3H), 1.91–1.76 (m, 1H), 1.48 (s, 1H), 1.17–1.08 (m, 1H); LCMS (electrospray) m / z 342.10 (M+H)+.

[0151] Synthesis method G

[0152] Example 55 (2-(dimethylamino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl) methyl ketone

[0153]

[0154] At 0°C, NaH (9 mg, 0.375 mmol, 2.5 equivalences) was added fractionally to a DMF (0.8 mL) solution of Example 5 (50 mg, 0.15 mmol, 1 equivalence). After 30 minutes, MeI (30 μl, 0.45 mmol, 3 equivalences) was added. The reaction mixture was stirred at 0°C for 2 hours. The mixture was then diluted with 10 mL of water and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0 to 8% gradient MeOH in DCM) to give Example 55 (18 mg, yield 33.7%).

[0155] 1¹H NMR (400MHz, DMSO-d⁶) δ 9.49 (t, J = 1.4Hz, 1H), 7.70–7.63 (m, 2H), 7.35 (dd, J = 13.7, 8.2Hz, 1H), 7.26 (t, J = 8.5Hz, 1H), 7.16 (d, J = 7.7Hz, 1H), 5.02 (dd, J = 67.3, 1.9Hz, 1H), 3.07 (d, J = 12.6Hz, 6H), 2.16 (d, J = 2.2Hz, 3H), 1.73–1.63 (m, 1H), 1.50 (td, J = 12.9, 6.4Hz, 1H); LCMS (electrospray) m / z 356.10 (M+H)+.

[0156] Synthesis method H

[0157] Example 70 (6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2- α]pyridin-2-yl)tert-butyl carbamate

[0158]

[0159] Step 1) tert-butyl dicarboxylate (6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-2-yl)dicarboxylate

[0160] At room temperature, TEA (0.414 mL, 3.04 mmol, 2 equivalents) and DMAP (92 mg, 0.76 mmol, 0.5 equivalents) were added to a 7 mL solution of THF (500 mg, 1.52 mmol, 1 equivalent) from Example 5, and the mixture was cooled to 0 °C. Boc anhydride (499 mg, 2.29 mmol, 1.5 equivalents) was then slowly added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate and washed with water, separated, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (the product was given at a hexane / ethyl acetate ratio of 1 / 2) to give compound 4 as a white solid (720 mg, 1.36 mmol, yield 89.8%).

[0161] Step 2) (6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-2-yl)tert-butyl carbamate

[0162] A solution of compound 4 (70 mg, 0.132 mmol, 1 equivalent) in DCM (1.30 mL) was cooled to 0 °C, and then TFA (0.101 mL, 1.32 mmol, 10 equivalents) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. After compound 4 was consumed, the reaction mixture was concentrated and neutralized with a saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, separated, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (the product was given at hexane / ethyl acetate = 4 / 6) to give the ivory solid of Example 70 (20 mg, 0.046 mmol, yield 35%).

[0163] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.85 (s, 1H), 9.47 (d, J = 1.2Hz, 1H), 7.80 (d, J = 9.2Hz, 1H), 7.68 (dd, J = 9.6, 2.0Hz, 1H), 7.38–7.33 (m, 1H), 7.27 (t, J = 8.8Hz, 1H), 7.20 (d, J = 7.6Hz, 1H), 5.06–4.83 (m, 1H), 2.91–2.83 (m, 1H), 2.17 (d, J = 2.0Hz, 3H), 1.91–1.80 (m, 1H), 1.46 (s, 9H), 1.28–1.21 (m, 1H); LCMS (electrospray) m / z 428.20 (M+H)+.

[0164] Synthesis Method I

[0165] Example 71 (6-(3-fluoro-2-methylphenyl)-2-(pyrrolidone-1-yl)imidazo[1,2-a]pyridin-3-yl) ((1S,2S)-2-fluorocyclopropyl)methyl ketone

[0166]

[0167] Under N2, DIPEA (157.94 mg, 1.22 mmol, 212.85 μL, 2 equivalents), DMAP (7.46 mg, 61.10 μmol, 0.1 equivalents), and 1,4-dibromobutane (791.55 mg, 3.67 mmol, 442.21 μL, 6 equivalents) were added to a toluene (3 mL) solution of Example 5 (200 mg, 611.01 μmol, 1 equivalent). The reaction mixture was stirred at 110 °C for 20 hours. Water (15 mL) was added, and the aqueous phase was extracted with EtOAc (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 2) and concentrated under vacuum. The crude product was purified by reversed-phase rapid chromatography (MeCN / H2O, 0.05% FA, 70%-85%) to obtain a pale yellow solid, Example 71 (19.8 mg, 50.20 μmol, yield 8.22%, purity 96.7%).

[0168] 1 H NMR(400MHz,DMSO-d6)δ9.64-9.51(m,1H),8.44(br s,1H),7.64-7.55(m,2H),7.42-7.30(m,1H),7.29-7.22(m,1H),7.17(d,J=7.2Hz,1H),5.37-4.94(m,1H),4.05-3.73(m,2H),2.19(br s, 1H), 2.16 (d, J = 2.3 Hz, 3H), 2.08 (s, 2H), 2.04-1.96 (m, 2H), 1.92 (brdd, J = 3.4, 6.3 Hz, 1H), 1.87-1.79 (m, 2H), 1.30-1.11 (m, 1H); LCMS (electrospray) m / z 382.00 (M+H)+.

[0169] Synthesis Method J

[0170] Example 87 (6-(3-fluoro-2-methylphenyl)-2-((2-(methylamino)ethyl)amino)imidazo[1,2-a]) Pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone

[0171]

[0172] Step 1)(2-((6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-2-yl)amino)ethyl)(methyl)carbamate tert-butyl

[0173] At room temperature, PPh3 (183 mg, 0.701 mmol, 1.5 equivalence) and tert-butyl (2-hydroxyethyl)(methyl)carbamate (81 mg, 0.467 mmol, 1 equivalence) were added to a 3 mL solution of THF (300 mg, 0.701 mmol, 1.5 equivalence) from Example 70, and the mixture was cooled to 0 °C. DEAD (0.318 mL, 0.701 mmol, 1.5 equivalence) was then slowly added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate, washed with water, separated, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (the product was given at hexane / ethyl acetate = 6 / 4) to give compound 5 as a white solid (241 mg, 0.412 mmol, yield 88%).

[0174] Step 2)(6-(3-fluoro-2-methylphenyl)-2-((2-(methylamino)ethyl)amino)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone

[0175] A solution of compound 5 (100 mg, 0.171 mmol, 1 equivalent) in DCM (1.71 mL) was cooled to 0 °C, and then TFA (0.261 mL, 3.42 mmol, 20 equivalents) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. After compound 5 was consumed, the reaction mixture was concentrated and neutralized with a saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, separated, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (the product was given at DCM / methanol = 10 / 1) to give the ivory solid of Example 87 (37 mg, 0.096 mmol, yield 56%).

[0176] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.50 (br s, 1H), 7.57-7.51 (m, 2H), 7.36-7.31 (m, 1H), 7.26-7.17 (m, 2H), 5.27-5.07 (m, 1H), 3.58 (q, 6.0Hz, 2H), 2.76 (t, J = 6.0Hz, 2H), 2.63-2.52 (m, 1H), 2.33 (s, 3H), 2.17 (d, J = 1.6Hz, 3H), 1.89-1.79 (m, 1H), 1.24-1.10 (m, 1H); LCMS (electrospray) m / z 385.15 (M+H)+.

[0177] Synthesis method K

[0178] Example 88 N-(6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo [1,2-a]pyridin-2-yl)acetamide

[0179]

[0180] Acetic anhydride (49 mg, 0.48 mmol, 2.0 equivalence), DMAP (29 mg, 0.12 mmol, 0.5 equivalence), and DIPEA (62 mg, 0.49 mmol, 2.0 equivalence) were added to a 3 mL solution of DCM (78 mg, 0.24 mmol, 1 equivalence) in Example 5. The mixture was stirred at 25 °C for 16 hours. The mixture was separated between the DCM and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, separated, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (the product was obtained in hexane / ethyl acetate = 1 / 1) to give an ivory-like solid of Example 88 (19 mg, 0.051 mmol, yield 21%).

[0181] 1H NMR (400MHz, DMSO-d6) δ 10.56 (s, 1H), 9.51 (d, J = 1.1Hz, 1H), 7.83 (d, J = 8.8Hz, 1H), 7.70 (dd, J = 9.3, 1.6Hz, 1H), 7.43-7.32 (m, 1H), 7.28 (t, J = 9.1Hz, 1H), 7.21 (d, J = 7.7Hz, 1H), 5.12-4.82 (m, 1H), 2.87-2.73 (m, 1H), 2.18 (d, J = 2.2Hz, 3H), 2.16 (s, 3H), 1.92-1.75 (m, 1H), 1.30-1.13 (m, 1H); LCMS (electrospray) m / z 370.10 (M+H)+.

[0182] Synthesis method L

[0183] Example 89 (2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S, 2S)-2-fluorocyclopropyl)methyl ketone

[0184]

[0185] Step 1)(2-amino-6-bromoimidazolo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone

[0186] To a DCM (500 mL) solution of 6-bromoimidazolo[1,2-a]pyridine-2-amine (5.81 g, 27.4 mmol, 1 equivalent), EDCI (7.88 g, 41.1 mmol, 1.5 equivalent), HOBt (6.29 g, 41.1 mmol, 1.5 equivalent), and TEA (4.16 g, 41.1 mmol, 5.73 mL, 1.5 equivalent) were added. The mixture was stirred at 25 °C for 1 hour, followed by the addition of (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (3.42 g, 32.9 mmol, 1.2 equivalent). The mixture was stirred at 25 °C for 11 hours. The reaction mixture was concentrated under reduced pressure to remove the DCM solution, yielding a residue. The crude product (hexane / ethyl acetate = 1 / 2) was purified by silica gel chromatography to give Example 2 a white solid (6.03 g, 19.62 mmol, yield 71.6%).

[0187] 1¹H NMR (400MHz, DMSO-d⁶) δ 9.69 (s, 1H), 7.63 (d, J = 9.2Hz, 1H), 7.34 (d, J = 10Hz, 1H), 6.71 (s, 2H), 5.25–5.06 (m, 1H), 2.62–2.51 (m, 1H), 1.91–1.80 (m, 1H), 1.18–1.09 (m, 1H); LCMS (electrospray) m / z 299.00 (M+H)+.

[0188] Step 2)(2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone

[0189] At room temperature, 4,4,4',4',5,5,5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (3.32 g, 13.08 mmol, 1.3 equivalent), Pd(dppf)Cl2 (736 mg, 1.00 mmol, 0.1 equivalent), and KOAc (2.96 g, 30.20 mmol, 3 equivalent) were added to a 50 mL solution of dioxane (Example 2) and heated at 90 °C for 7 hours. The mixture was then cooled to room temperature, filtered through a diatomaceous earth mat to remove solids, and separated between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, separated, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 1 / 2) to give compound 6 as a beige solid (1.9 g, 5.504 mmol, yield 54.7%).

[0190] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.83 (s, 1H), 7.59 (d, J = 9.0Hz, 1H), 7.32 (d, J = 9.7Hz, 1H), 6.73 (s, 2H), 5.23–5.05 (m, 1H), 2.51–2.50 (m, 1H), 1.90–1.81 (m, 1H), 1.31 (s, 9H), 1.15–1.06 (m, 1H); LCMS (electrospray) m / z 346.10 (M+H)+, 264.10 (M-82)+.

[0191] Step 3)(2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone

[0192] At room temperature, 5-bromo-4-methyl-1H-indole (365 mg, 1.738 mmol, 1 equivalent), Na₂CO₃ (553 mg, 5.21 mmol, 3 equivalent), and Pd(dppf)Cl₂ (127 mg, 0.174 mmol, 0.1 equivalent) were added to a solution of compound 6 (600 mg, 1.738 mmol, 1 equivalent) in dioxane (7 mL) and water (1.75 mL). The mixture was then heated in a microwave at 100 °C for 1 hour, cooled to room temperature, filtered through a diatomaceous earth mat to remove the solid, and separated between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, separated, dried over anhydrous MgSO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 1 / 1) to give the ivory-like solid of Example 89 (121 mg, 0.347 mmol, yield 19.9%).

[0193] 1 H NMR (400MHz, DMSO-d6) δ 11.15 (s, 1H), 9.47 (s, 1H), 7.50 (dd, J = 9.1, 1.9Hz, 1H), 7.41-7.32 (m, 2H), 7.28 (d, J = 8.2Hz, 1H), 6.98 (d, J = 8.2Hz, 1H), 6.53 (d, J = 33.0Hz, 3H), 5.30-4.98 (m, 1H), 2.60-2.49 (m, 1H), 2.38 (s, 3H), 1.90-1.68 (m, 1H), 1.11-0.96 (m, 1H); LCMS (electrospray) m / z 349.10 (M+H)+.

[0194] Synthesis method M

[0195] Example 99 (2-amino-8-fluoro-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S, 2S)-2-fluorocyclopropyl)methyl ketone

[0196]

[0197] Step 1) N-(5-bromo-3-fluoropyridin-2-yl)-4-methylbenzenesulfonamide

[0198] At 20 °C, TsCl (10.98 g, 57.59 mmol, 1.1 equivalence) was added to a solution of 5-bromo-3-fluoropyridine-2-amine (10 g, 52.36 mmol, 1 equivalent) in pyridine (100 mL). The mixture was stirred at 90 °C for 16 h. The mixture was diluted with NaHCO3 (200 mL) and extracted with ethyl acetate (300 mL). The organic layer was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1). Compound 7 (10 g, 28.97 mmol, yield 55.33%) was given as a yellow solid.

[0199] Step 2) (E)-2-(5-bromo-3-fluoro-2-(tolylamino)pyridine-1(2H)-yl)acetamide

[0200] To a DMF (10 mL) solution of compound 7 (9 g, 26.07 mmol, 1 equivalent), DIPEA (3.71 g, 28.68 mmol, 5.00 mL, 1.1 equivalent) and 2-bromoacetamide (3.96 g, 28.68 mmol, 1.1 equivalent) were added. The mixture was stirred at 20 °C for 16 hours. The mixture was concentrated to give compound 8 (10 g, crude product) as a brown solid.

[0201] Step 3) N-(6-bromo-8-fluoroimidazole[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide

[0202] TFAA (31.33 g, 149.17 mmol, 20.75 mL, 12 equivalents) was added to a DCE (10 mL) solution of compound 8 (5 g, 12.43 mmol, 1 equivalent). The mixture was stirred at 60 °C for 3 h. The mixture was neutralized with saturated NaHCO3 and extracted with ethyl acetate (300 mL). The organic layer was concentrated. The residue was purified by reversed-phase rapid chromatography (0.1% FA conditions, 5-70% water / MeCN) and lyophilized to give compound 9 (2 g, 6.13 mmol, yield 24.67%) as a yellow solid.

[0203] Step 4) 8-Fluoro-6-(3-Fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-2-amine

[0204] To a solution of compound 9 (0.5 g, 1.53 mmol, 1 equivalent) in dioxane (4 mL) and H₂O (1 mL), (3-fluoro-2-methylphenyl)boronic acid (283.30 mg, 1.84 mmol, 1.2 equivalent), Pd(dppf)Cl₂ (112.21 mg, 153.35 μmol, 0.1 equivalent), and Na₂CO₃ (487.61 mg, 4.60 mmol, 3 equivalent) were added. The mixture was stirred at 90 °C for 16 h and concentrated. The residue was purified by reversed-phase rapid chromatography (0.1% FA conditions, 5-70% water / MeCN) and lyophilized to give compound 10 (0.35 g, 1.35 mmol, yield 88.03%) as a white solid.

[0205] Step 5)(2-amino-8-fluoro-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone

[0206] To a DCM (4 mL) solution of compound 10 (60.22 mg, 578.58 μmol, 1 equivalent), EDCI (133.10 mg, 694.30 μmol, 1.2 equivalent), HOBt (93.82 mg, 694.30 μmol, 1.2 equivalent), and TEA (70.26 mg, 694.30 μmol, 96.64 μL, 1.2 equivalent) were added. The mixture was stirred at 20 °C for 1 hour, and then (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (0.15 g, 578.58 μmol, 1 equivalent) was added. The mixture was stirred at 20 °C for 15 hours and concentrated. The residue was purified by reversed-phase rapid chromatography (0.1% FA conditions, 5-70% H2O / MeCN) and then lyophilized to obtain Example 99 (68 mg, 185.50 μmol, yield 32.06%, purity 94.2%, white solid).

[0207] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.35 (s, ¹H), 7.62–7.59 (m, ¹H), 7.36–7.19 (m, ³H), 6.87 (s, ¹H), 5.29–5.10 (m, ¹H), 2.61–2.52 (m, ¹H), 2.19 (s, ³H), 1.89–1.84 (m, ¹H), 1.17–1.13 (m, ¹H); LCMS (electrospray) m / z 346.10 (M+H)+.

[0208] Synthesis method N

[0209] Example 107 2-Amino-N-cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-methylimidazo[1,2-a]pyridine Pyridine-3-carboxamide

[0210]

[0211] Step 1) 6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-2-amine

[0212] To a solution of 6-bromoimidazolo[1,2-a]pyridine-2-amine (324 mg, 1.53 mmol, 1 equivalent) in dioxane (4 mL) and H₂O (1 mL), (3-fluoro-2-methylphenyl)boronic acid (283.30 mg, 1.84 mmol, 1.2 equivalent), pd(dppf)Cl₂ (112.21 mg, 153.35 μmol, 0.1 equivalent), and Na₂CO₃ (487.61 mg, 4.60 mmol, 3 equivalent) were added. The mixture was stirred at 90 °C for 16 h. The mixture was concentrated. The residue was purified by reversed-phase rapid chromatography (0.1% FA conditions, 5-70% H₂O / MeCN) and lyophilized to give compound 11 as a white solid (107 mg, 1.07 mmol, yield 70.00%).

[0213] Step 2 (6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)carbamate di-tert-butyl

[0214] At room temperature, a solution of compound 11 (500 mg, 2.07 mmol, 1 equivalent) in THF (10 mL) was treated with TEA (0.577 mL, 4.14 mmol, 2 equivalents) and DMAP (126 mg, 1.03 mmol, 0.5 equivalents), and then cooled to 0 °C. Boc anhydride (903 mg, 4.14 mmol, 2.0 equivalents) was then slowly added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate and washed with water, separated, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 6 / 4) to give compound 12 (445 mg, 1.00 mmol, 48% yield) as a white solid.

[0215] Step 3) 2-(di(tert-butoxycarbonyl)amino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxylic acid

[0216] A solution of compound 12 (200 mg, 0.453 mmol, 1 equivalent) in THF (2.26 mL) was cooled to -78 °C, and LDA (0.906 mL, 1.81 mmol, 4 equivalents) was added dropwise. The mixture was then stirred at the same temperature for 30 min. Dry ice was added fractionally, and the reaction mixture was stirred at -78 °C for 2 h. The reaction mixture was then quenched with ice, extracted with DCM, and the combined organic phases were washed with water (100 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (DCM / methanol = 10 / 1) to give compound 13 (81 mg, 0.166 mmol, yield 36%) as a white solid.

[0217] Step 4) (3-(cyclopropyl(methyl)carbamoyl)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)carbamate di-tert-butyl

[0218] To a solution of compound 13 (81 mg, 0.164 mmol, 1 equivalent) in DMF (0.8 mL), N-methylcyclopropylamine (17 mg, 0.247 mmol, 1.5 equivalent), EDCI (62 mg, 0.328 mmol, 2.0 equivalent), HOBt (44 mg, 0.328 mmol, 2 equivalent), and TEA (0.068 mL, 0.492 mmol, 3 equivalent) were added, and the mixture was stirred at 50 °C for 2 h. The reaction mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (hexane / ethyl acetate = 6 / 4) to give compound 14 (49 mg, 0.090 mmol, 55% yield) as a white solid.

[0219] Step 5) 2-Amino-N-cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide

[0220] To a solution of compound 14 (45 mg, 0.083 mmol, 1 equivalent) in DCM (0.4 mL), 4N HCl dioxane (0.2 mL, 0.835 mmol, 10 equivalents) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After compound 14 was consumed, the reaction mixture was concentrated and neutralized with a saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, separated, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (DCM / methanol = 8 / 1) to give the ivory solid of Example 107 (22 mg, 0.065 mmol, 78% yield).

[0221] 1H NMR (400MHz, DMSO-d6) δ 8.49 (s, 1H), 7.35-7.25 (m, 3H), 7.21 (t, J = 9.0Hz, 1H), 7.14 (d, J = 7.2Hz, 1H), 5.71 (s, 2H), 2.94 (s, 3H), 2.91-2.84 (m, 1H), 2.16 (s, 3H), 0.60-0.51 (m, 4H); LCMS (electrospray) m / z 339.10 (M+H)+.

[0222] Synthesis method O

[0223] Example 112N'-acetyl-2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carbazide

[0224]

[0225] To a DCM (0.8 mL) solution of compound 13 (84 mg, 0.155 mmol, 1 equivalent), acetylhydrazine (13.7 mg, 0.186 mmol, 1.2 equivalent), EDCI (46 mg, 0.232 mmol, 1.5 equivalent), and HOBt (31.4 mg, 0.232 mmol, 1.5 equivalent) were added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was extracted with DCM (3 mL), and the combined organic phases were washed with 1 N HCl aqueous solution (3 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 8 / 2) to give Example 112 (4.6 mg, 0.013 mmol, yield 8.6%) as a white solid.

[0226] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.82 (s, 1H), 9.10 (s, 1H), 9.06 (t, J = 1.4Hz, 1H), 7.39 (d, J = 1.1Hz, 2H), 7.33–7.16 (m, 3H), 6.18 (s, 2H), 2.16 (d, J = 2.2Hz, 3H), 1.90 (s, 3H); LCMS (electrospray) m / z 342.10 (M+H)+.

[0227] Synthesis method P

[0228] Example 135 Methyl 2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxylic acid

[0229]

[0230]

[0231] Step 1) N-(6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)acetamide

[0232] To a DCM (3 mL) solution of compound 11 (58 mg, 0.24 mmol, 1 equivalent), acetic anhydride (49 mg, 0.48 mmol, 2.0 equivalent), DMAP (29 mg, 0.12 mmol, 0.5 equivalent), and DIPEA (62 mg, 0.48 mmol, 2.0 equivalent) were added. The mixture was stirred at 25 °C for 16 hours. The mixture was separated between DCM and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, separated, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 1 / 1) to give compound 15 (38 mg, 0.13 mmol, 56% yield) as an ivory solid.

[0233] Step 2) N-(3-bromo-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)acetamide

[0234] N-bromosuccinimide (18.6 mg, 0.105 mmol, 1 equivalence) was added to a solution of compound 15 (30 mg, 0.105 mmol, 1 equivalence) in MeCN (1 mL), and the mixture was stirred at 0 °C for 2 h. The reaction mixture was extracted with DCM (3 mL), the combined organic phases were washed with H2O, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. Compound 16 (32 mg, 0.09 mmol, 86% yield) was given as an ivory solid.

[0235] Step 3) Methyl 2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxylic acid

[0236] To a solution of compound 16 (300 mg, 828.28 μmol, 1 equivalent) in MeOH (10 mL), TEA (252 mg, 2.48 mmol, 346 μL, 3 equivalents) and Pd(dppf)Cl2 (61 mg, 82.83 μmol, 0.1 equivalents) were added, and the reaction mixture was stirred at 80 °C under a CO atmosphere (50 psi) for 12 h. The reaction mixture was filtered and concentrated to give the residue. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1 to 0:1) Prep HPLC (column: Waters Xbridge 150*25mm*5µm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%-63%, 9 min) and then lyophilized. Example 135: A white solid was obtained (5.2 mg, 17.37 μmol, yield 2.10%, purity 100%).

[0237] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.93 (br s, 1H), 7.48–7.43 (m, 1H), 7.42–7.38 (m, 1H), 7.37–7.30 (m, 1H), 7.27–7.21 (m, 1H), 7.17 (d, J = 7.7Hz, 1H), 6.40 (s, 2H), 3.82 (s, 3H), 2.17 (d, J = 2.3Hz, 3H); LCMS (electrospray) m / z 300.10 (M+H)+

[0238] Synthesis method Q

[0239] Example 148 (2-amino-6-((3-fluoro-2-methylphenyl)amino)imidazo[1,2-a]pyridin-3-yl) ((1S,2S)-2-fluorocyclopropyl)methyl ketone

[0240]

[0241] Step 1) 2,2,2-Trifluoro-N-(6-((3-fluoro-2-methylphenyl)amino)imidazo[1,2-a]pyridin-2-yl)acetamide

[0242] To a solution of N-(6-bromoimidazolo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide (500 mg, 1.62 mmol, 1 equivalent) and 3-fluoro-2-methylaniline (243.74 mg, 1.95 mmol, 221.58 μL, 1.2 equivalent) in 1,4-dioxane (10 mL), BrettPhos Pd G3 (147.13 mg, 162.31 μmol, 0.1 equivalent) and t-BuONa (2 M, 1.62 mL, 2 equivalent) were added. The mixture was stirred at 90 °C under N2 for 12 hours. The reaction mixture was separated between ethyl acetate (100 mL x 3) and H2O (100 mL x 3). The organic phase was separated, washed with NaCl (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 0 / 1). The brown, gelatinous compound 17 was given (100 mg, 283.86 μmol, yield 17.49%).

[0243] Step 2) N6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-2,6-diamine

[0244] K₂CO₃ (117.69 mg, 851.58 μmol, 3 equivalents) was added to a solution of compound 17 (100 mg, 283.86 μmol, 1 equivalent) in MeOH (5 mL) and H₂O (1 mL). The mixture was stirred at 70 °C for 12 h. The reaction mixture was separated between ethyl acetate (50 mL x 3) and H₂O (50 mL x 3). The organic phase was separated, washed with NaCl (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 3 / 1 to 0 / 1). Compound 18 (20 mg, 78.04 μmol, yield 27.49%) was given as a brown solid.

[0245] Step 3)(2-amino-6-((3-fluoro-2-methylphenyl)amino)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone

[0246] To a solution of compound 18 (20 mg, 78.04 μmol, 1 equivalent) and (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (8.12 mg, 78.04 μmol, 1 equivalent) in DCM (3 mL), EDCI (14.96 mg, 78.04 μmol, 1 equivalent) and HOBt (10.55 mg, 78.04 μmol, 1 equivalent) were added. The mixture was stirred at 25 °C for 12 h. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0-1 / 1), and the crude product was purified by reversed-phase HPLC (0.1% FA conditions). Example 148 (0.5 mg, 1.46 μmol, yield 1.87%) was given as a brown solid.

[0247] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.46-9.28 (m, 1H), 7.57 (s, 1H), 7.37-7.33 (m, 1H), 7.33-7.29 (m, 1H), 7.09-7.02 (m, 1H), 6.74-6.70 (m, 1H), 6.68-6.65 (m, 1H), 6.42 (br s, 1H), 5.25-5.01 (m, 1H), 2.12 (d, J = 1.59Hz, 3H), 1.88-1.75 (m, 1H), 1.14-1.02 (m, 2H); LCMS (electrospray) m / z 343.10 (M+H)+.

[0248] Synthesis method R

[0249] Example 151 (3S,4R)-4-methyltetrahydrofuran-3-yl-2-amino-6-(5-chloro-6-fluoro-7-(methylthio)- 1H-Indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxylic acid ester

[0250]

[0251] Step 1) N-(6-(5-chloro-6-fluoro-7-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide

[0252] At 20 °C and under N2, Pd(dppf)Cl2 (97 mg, 132.00 μmol, 0.1 equivalent) and Na2CO3 (420 mg, 3.96 mmol, 3 equivalent) were added in a single batch to a mixture of compound 2 (938 mg, 2.64 mmol, 2 equivalent) and 4-bromo-5-chloro-6-fluoro-7-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (500 mg, 1.32 mmol, 1 equivalent) in dioxane (25 mL) and H2O (5 mL). The mixture was heated to 80 °C and stirred for 3 hours. The reaction mixture was filtered, diluted with H2O (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1). A red oily compound 19 was given (400 mg, 757.69 μmol, yield 57.40%).

[0253] Step 2) 6-(5-chloro-6-fluoro-7-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-2-amine

[0254] At 20 °C and under N2, K2CO3 (458 mg, 3.31 mmol, 5 equivalences) was added in a single batch to a mixture of compound 19 (350 mg, 662.98 μmol, 1 equivalent) in MeOH (20 mL) and H2O (5 mL). The mixture was heated to 70 °C for 16 hours. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The crude product was purified by reversed-phase HPLC (0.1% FA conditions). Compound 20 (118 mg, 273.20 μmol, yield 41.21%) was given as a brown solid.

[0255] Step 3)(3S,4R)-4-methyltetrahydrofuran-3-yl-2-amino-6-(5-chloro-6-fluoro-7-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxylic acid ester

[0256] At 20 °C and under N2, DIPEA (144 mg, 1.11 mmol, 193.57 μL, 6 equivalents) was added in a single batch to a mixture of compound 20 (80 mg, 185.22 μmol, 1 equivalent) and (3S,4R)-4-methyltetrahydrofuran-3-yl(4-nitrophenyl) carbonate (248 mg, 926.10 μmol, 5 equivalents) in THF (10 mL). The mixture was then heated to 80 °C and stirred for 24 hours. The reaction mixture was cooled to 20 °C, quenched with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with NaCl solution (30 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give compound 21 (54 mg, crude), which is a yellow oil.

[0257] Step 4) (3S,4R)-4-methyltetrahydrofuran-3-yl-2-amino-6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxylic acid ester

[0258] At 0 °C and under N2, HCl / dioxane (4 M, 0.5 mL, 20.74 equivalents) was added dropwise to a mixture of compound 21 (54 mg, 96.42 μmol, 1 equivalent) in dioxane (2 mL). The mixture was stirred at 0 °C for 0.1 h. The reaction mixture was quenched at 0 °C by adding Et3N / MeOH (0.5 mL / 0.5 mL) and then concentrated under reduced pressure to give the residue. The crude product was purified by reversed-phase HPLC (0.1% FA conditions). Example 151 (5.1 mg, 10.72 μmol, yield 11.11%) was given as a brown solid.

[0259] 1 H NMR (400MHz, DMSO-d6) δ 13.82 (s, 1H) 9.15 (s, 1H) 8.08 (s, 1H) 7.64 (d, J = 9.11, 1H) 7.53 (d, J = 9.05Hz, 1H) 6.29-6.56 (m, 2H) 5.01-5.10 (m, 1H) 3.80-4.03 (m, 4H) 2.56-2.64 (m, 4H) 1.05 (d, J = 7.09Hz, 3H); LCMS (electrospray) m / z 476.00 (M+H)+.

[0260] Synthesis method S

[0261] Example 153 (2-amino-5-(6-fluoro-5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl) (cyclopropyl) methyl ketone

[0262]

[0263] Step 1) N-(5-bromo-3-(cyclopropanecarbonyl)pyrazolo[1,5-a]pyridin-2-yl)-2,2,2-trifluoroacetamide

[0264] At room temperature, cyclopropaneyl chloride (81 mg, 0.78 mmol, 1.2 equivalence) and TiCl4 (493 mg, 2.601 mmol, 4.0 equivalence) were added to a solution of N-(5-bromopyrazolo[1,5-a]pyridin-2-yl)-2,2,2-trifluoroacetamide (200 mg, 0.65 mmol, 1.0 equivalence) in DCM (13 mL), and the mixture was heated at 80 °C for 16 h. The mixture was cooled to room temperature, quenched with saturated NaHCO3, and extracted with DCM (3 x 100 mL). The organic layer was washed with saturated aqueous sodium chloride solution, separated, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 3 / 1) to give compound 22 as a brown solid (169 mg, 0.449 mmol, yield 69%).

[0265] 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),8.84(dd,J=7.1,2.2Hz,1H),8.38(d,J=2.2Hz,1H ),7.40(dd,J=7.7,2.2Hz,1H),2.56-2.48(m,1H),1.09-1.00(m,2H),1.00-0.93(m,2H).

[0266] Step 2)(2-amino-5-(6-fluoro-5-methyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)(cyclopropyl) methyl ketone

[0267] At room temperature, a solution of compound 22 (80 mg, 0.21 mmol, 1.0 equivalence) in dioxane (2 mL) and H₂O (1 mL) was added to 6-fluoro-5-methyl-2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-2H-indazole (115 mg, 0.32 mmol, 1.5 equivalence), Na₂CO₃ (45 mg, 0.43 mmol, 2.0 equivalence), and Pd(dppf)Cl₂ (16 mg, 0.02 mmol, 0.1 equivalence), and then heated at 100 °C for 16 hours. The mixture was cooled to room temperature, filtered through a diatomaceous earth mat to remove solids, and separated between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride, separated, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 1 / 1) to give compound 23 (44 mg, 0.101 mmol, 48% yield) as an ivory-like solid.

[0268] 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=7.7Hz,1H),7.94(d,J=1.1Hz,1H),7.85(s,1H),7.70(d,J =10.4Hz,1H),7.01(dd,J=6.7,2.1Hz,1H),6.66(s,2H),5.84(dd,J=9.9,2.7Hz,1H),3.94-3. 84(m,1H),3.84-3.69(m,1H),2.49-2.45(m,1H),2.45-2.30(m,1H),2.24(d,J=2.7Hz,3H),2. 13-1.89(m,2H),1.84-1.66(m,1H),1.66-1.50(m,2H),1.05-0.91(m,2H),0.91-0.80(m,2H).

[0269] Step 3)(2-amino-5-(6-fluoro-5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)(cyclopropyl) methyl ketone

[0270] TFA (316 mg, 2.77 mmol, 30.0 equivalence) was added to a DCM (1 mL) solution of compound 23 (40 mg, 0.09 mmol, 1.0 equivalence). The mixture was stirred at 25 °C for 3 hours. The reaction mixture was adjusted to pH 7 with a saturated aqueous solution of NaHCO3. The mixture was diluted with water (20 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 1 / 3) to give the ivory solid of Example 153 (21.2 mg, 0.061 mmol, yield 66%).

[0271] 1 H NMR (400MHz, DMSO-d6) δ 13.23 (s, 1H), 8.66 (d, J = 6.6Hz, 1H), 7.95 (s, 1H), 7.81 (s, 1H), 7.42 (d, J = 9.9Hz, 1H), 7.02 (dd, J = 7.1, 1.6Hz, 1H), 6.66 (s, 2H), 2.49–2.43 (m, 1H), 2.24 (d, J = 2.7Hz, 3H), 1.03–0.92 (m, 2H), 0.92–0.82 (m, 2H); LCMS (electrospray) m / z 350.10 (M+H)+.

[0272] Table 1 below shows the compounds of the examples, as well as the general synthetic methods and characterization data used to prepare the compounds.

[0273] Table 1 Compounds in Examples

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304] Compound evaluation here

[0305] RIP2 kinase assay

[0306] GST-labeled recombinant human RIP2 (25 ng) was incubated in buffer (40 mM Tris, 7.5; 20 mM MgCl2; 0.1 mg / mL BSA; 50 μM DTT) with 5 μL of compound (0.5% DMSO), 5 μL of MBP (0.5 μg / μL), and 5 μL of ATP (25 μM). Assay was initiated by incubating the reaction mixture in a 96-well plate at 30 °C for 60 min. After incubation, 25 μL of ADP-Glo ​​reagent was added, and the reaction was incubated at 30 °C for 40 min to terminate the reaction and degrade residual ATP. The ADP product was then converted to ATP by adding 50 μL of assay reagent to each well. After incubation at room temperature for 30 min, luminescence was detected using a Molecular device I3X plate reader. IC50 was calculated based on a series of inhibition percentage values ​​using a software program implemented in GraphPad Prism 7 and SigmaPlot 13.0. 50 The values ​​are obtained by measuring the percentage of inhibition within a range of inhibitor concentrations.

[0307] c-Abl kinase assay

[0308] The ADP-Glo ​​assay kit was purchased from Promega. Magnesium chloride (MgCl2), bovine serum albumin (BSA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), Tween-20, 1,4-dithiothreitol (DTT), and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich. HEPES buffer was purchased from Gibco. ABL1 kinase and Abltide were purchased from Signalchem.

[0309] c-Abl kinase activity is mediated by Promega's ADP-Glo TMAssay. In this assay, His-labeled recombinant human ABL1 (0.25 ng / μl) was incubated in buffer (50 mM HEPES, 7.5; 10 mM MgCl2; 1 mM EGTA; 0.05% BSA; 0.01% Tween-20; 2 mM DTT) with 5 μL of compound (0.5% DMSO), 5 μL of ablide (0.01 μg / μl), and 5 μL of ATP (25 μM). The assay was initiated by incubating the reaction mixture in a 96-well plate at 30 °C for 30 min. After incubation, 25 μL of ADP-Glo ​​reagent was added, and the reaction was incubated at room temperature for 40 min to terminate the reaction and degrade residual ATP. The ADP product was then converted to ATP by adding 50 μL of assay reagent to each well. After incubation at room temperature for 30 min, luminescence was detected using a Molecular device I3X plate reader. The IC was calculated using a software program implemented in GraphPad Prism 7 and SigmaPlot 13.0, based on a series of suppression percentage values. 50 The values ​​are obtained by measuring the percentage of inhibition within a range of inhibitor concentrations.

[0310] BV-2 cells secrete IL-6

[0311] BV-2 mouse microglia were kindly provided by Dr. Bae of the Korea Advanced Institute of Science and Technology (KIST). The BV-2 cells were thawed and suspended in Dulbecco modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin. The cells were then cultured at 2 x 10⁻⁶ cells / day. 4 Cells were seeded at a density of 10 cells / well in 96-well plates and allowed to adhere for 24 hours. On the day of the experiment, cells were treated with different concentrations of FB compound and stimulated with 10 μg / ml L18-MDP. After 24 hours of incubation, the supernatant was collected for cytokine assay.

[0312] Twenty-four hours after stimulation, cytokine secretion was measured using an IL-6 ELISA kit (R&D system) as recommended by the manufacturer. Absorbance at 450 nm was measured using a SpectraMax i3X microplate reader. Values ​​from wells containing only culture medium were subtracted, and the percentage of inhibition for each compound concentration relative to the DMSO / L18-MDP-treated control (100%) was calculated. IC50 was calculated based on a series of activity percentage values ​​using software implemented in GraphPad Prism 7 and SigmaPlot 13.0. 50 value.

[0313] Table 2 shows the IC50 of the compounds of the present invention. 50The values ​​are: + indicates >1000nM, ++ indicates 501-1000nM, +++ indicates 101-500nM, and ++++ indicates 1-100nM.

[0314] Table 2. In vitro kinase activity and IL-6 secretion of BV-2 cells.

[0315]

[0316]

[0317]

[0318]

[0319] -; Not tested.

Claims

1. A compound as shown in formula (I): Or its pharmaceutically acceptable salt, wherein: R 1 and R 2 Independently -H, C1-C6 alkyl, or C1-C4 alkylyl, wherein each R 1 and R 2 Optionally substituted with one or more groups selected from methylaminomethyl and ethylaminomethyl; or R 1 and R 2 Together they form a 5-membered heterocyclic ring; R 3 Selected from methyl, butyl, methoxy, pyridyl, phenyl, cyclopropyl, cyclobutyl, pyrazolyl, aziridine, pyrimidinyl, pyrrolidinyl, cyclopropylamino, and tetrahydrofuranyl, wherein R 3 Optionally selected by one or more halogens, and C1-C 12 Alkyl group substitution; R 4 and R 5 Independently -H, or halogen; R 6 Selected from bromoyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, pyrroloyl, imidazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrrolopyridyl, imidazoolopyridyl, indazole, benzimidazolyl, quinolinyl, or isoquinolinyl, wherein R 6 Optionally selected by one or more elements chosen from halogens, hydroxyl groups, C1-C 12 Alkyl, C1-C 12 alkenyl, C1-C 12 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Substitution of alkylamino, morpholino, piperazine, and methylpiperazine groups; X is N; and Y is C.

2. The compound according to claim 1, characterized in that, Selected from: (2-amino-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(1H-indol-6-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(1H-indol-7-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-8-fluoro-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(4-chloro-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-8-fluoro-6-(1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(5-methyl-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(5-fluoro-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(5-chloro-1H-indol-3-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(6-fluoro-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(6-fluoro-5-methyl-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1R,2R)-2-fluorocyclopropyl) ketone; (2-amino-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2R)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1R,2R)-2-fluorocyclopropyl) ketone; (2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2R)-2-fluorocyclopropyl) ketone; 3-(2-amino-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-6-yl)-1H-indole-1-carboxylic acid tert-butyl ester; (2-amino-6-(1H-indol-3-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-bromoimidazolo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(4-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(thien-2-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(2-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-fluoro-2-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2,3-dimethylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(5-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2,5-dimethylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2,4-dimethylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-fluoro-6-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-methyl-3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(4-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-fluoro-6-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(furan-2-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(5-methylthiazo-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-methylthiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(thiazo-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3,4-difluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2R)-2-fluorocyclopropyl) ketone; 1-(4-(2-amino-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-6-yl)-3-methylphenyl)ethane-1-one; (2-amino-6-(4-morpholinophenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2R)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-chloro-3-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-methyl-5-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (S)-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(2,2-difluorocyclopropyl) ketone; (2-amino-6-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(4-(4-methylpiperazin-1-yl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-(4-methylpiperazin-1-yl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(7-(dimethylamino)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(6-fluoro-5-methyl-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(benzofuran-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(3-methylisothiazo-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(4-chloro-1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(4-methyl-1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-8-fluoro-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-8-fluoro-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(1H-benzo[d]imidazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(4-methyl-1H-benzo[d]imidazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; 2-Amino-6-(3-fluoro-2-methylphenyl)-N-((1R,2S)-2-fluorocyclopropyl)imidazo[1,2-a]pyridine-3-carboxamide; (2-amino-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[1,2-a]pyridin-3-alkyl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(quinolin-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(quinolin-3-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(isoquinoline-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(o-tolyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-(2-fluoroethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-fluoro-2-(2-fluoroethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; 2-(2-amino-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-6-yl)-1H-pyrrole-1-carboxylic acid tert-butyl ester; 3-(2-amino-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-6-yl)-1H-pyrrole-1-carboxylic acid tert-butyl ester; (2-amino-6-(3-fluoro-2-(3-hydroxypropyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(1H-pyrrolo-2-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(1H-pyrrolo-3-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(3-fluoro-2-(2-hydroxyethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-fluoro-2-(hydroxymethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-(2-hydroxyethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-(3-hydroxypropyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-(2-fluoroethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-fluoro-2-(3-fluoropropyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-(3-fluoropropyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-amino-5-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(4-amino-2-fluoro-5-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-fluoro-2-(2-fluoroethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-(2-amino-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-6-yl)benzyl)tert-butyl carbamate; (2-amino-6-(2-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-(2-fluoroethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2R)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-(2-fluoroethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-fluoro-2-(2-fluoroethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2R)-2-fluorocyclopropyl) ketone; (2-amino-6-(5-amino-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(2-amino-6-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-fluoro-2-((E)-2-methoxyvinyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-fluoro-2-vinylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) methyl ketone; (2-amino-6-(5-fluoro-2-methyl-3-(methylamino)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-(dimethylamino)-5-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-((3-fluoro-2-methylphenyl)amino)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-fluoro-2-(2-fluoroethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2R)-2-fluorocyclopropyl) ketone; (2-amino-6-(5-amino-3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-(3-fluoro-2-methylphenoxy)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-amino-6-bromoimidazolo[1,2-a]pyridin-3-yl)(cyclopropyl) methyl ketone; (2-amino-6-(4-methylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl](cyclopropyl) methyl ketone; (2-amino-6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)(cyclopropyl) ketone; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(cyclopropyl) ketone; 1-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)ethane-1-one; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl) methyl ketone; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(phenyl) methyl ketone; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(cyclobutyl) ketone; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(1-methyl-1H-pyrazol-4-yl) methyl ketone; 1-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)-2,2-dimethylpropane-1-one; 1-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)pentan-1-one; 2-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carbonyl)azacyclobutane-1-carboxylic acid tert-butyl ester; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(3,3-difluorocyclobutyl) ketone; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(azacyclobutane-2-yl) methyl ketone; 3-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carbonyl)azacyclobutane-1-carboxylic acid tert-butyl ester; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(azacyclobutane-3-yl) methyl ketone; (2-amino-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)methyl ketone; (2-amino-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)methyl ketone; (2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)methyl ketone; (2-amino-6-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)methyl ketone; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(pyrimidin-2-yl) methyl ketone; (2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(pyrimidin-4-yl) methyl ketone; (2-amino-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrimidin-4-yl) methyl ketone; (2-amino-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrimidin-2-yl)methyl ketone; (2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(azacyclobutane-3-yl) methyl ketone; (2-amino-6-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(azacyclobutane-3-yl) methyl ketone; (2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrimidin-4-yl)methyl ketone; (2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrimidin-2-yl)methyl ketone; (2-amino-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(azacyclobutane-3-yl) methyl ketone; (2-amino-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrrolidin-3-yl) methyl ketone; (2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrrolidin-3-yl) methyl ketone; (2-amino-6-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrrolidin-3-yl) methyl ketone; 2-Amino-N-cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide; 2-Amino-N-cyclopropyl-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide; N'-acetyl-2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carbazide; 2-Amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxylic acid methyl ester; 2-Amino-6-(5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl)-N-cyclopropylimidazo[1,2-a]pyridine-3-carboxamide; (3S,4R)-4-methyltetrahydrofuran-3-yl2-amino-6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxylic acid ester; (2-((2-(dimethylamino)ethyl)amino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-((2-aminoethyl)amino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; N-acetyl-N-(3-acetyl-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)acetamide; (6-(3-fluoro-2-methylphenyl)-2-(methylamino)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (2-(dimethylamino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl) ketone; (6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-2-yl)tert-butyl carbamate; (6-(3-fluoro-2-methylphenyl)-2-(pyrrolidone-1-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; (6-(3-fluoro-2-methylphenyl)-2-((2-(methylamino)ethyl)amino)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl) ketone; N-(6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-2-yl)acetamide; and N-(3-acetyl-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)acetamide.

3. The compound according to any one of claims 1 or 2, characterized in that, The salt is a hydrochloride, tartrate, phosphate, or maleate.

4. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4, characterized in that, It also contains one or more active ingredients that can be used to treat neurodegenerative diseases.

6. The use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 4 to 5, in the preparation of a medicament for treating diseases associated with RIPK2 and / or c-abl kinase, characterized in that, The disease is an inflammatory or autoimmune disease, selected from alpha-synucleinosis, Parkinson's disease, Lewy body dementia, multiple system atrophy, Alzheimer's disease, and amyotrophic lateral sclerosis.

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